[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: 94-2264]


[[Page Unknown]]

[Federal Register: February 2, 1994]


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Part VI





Department of Health and Human Services





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Food and Drug Administration



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21 CFR Part 331



Antacid Drug Products for Over-the-



Counter Human Use; Amendment to Antacid Final Monograph; Proposed Rule
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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 331

[Docket No. 93N-0164]
RIN 0905-AA06

 

Antacid Drug Products for Over-the-Counter Human Use; Proposed 
Amendment of Antacid 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 proposing to amend 
the final monograph for over-the-counter (OTC) antacid drug products to 
require specific indication, warning, and direction statements in the 
labeling of products containing sodium bicarbonate as an active 
ingredient. The new labeling would be required only for oral dosage 
forms intended to be dissolved in liquid prior to administration, such 
as powders and effervescent granules or tablets. As proposed, no such 
oral dosage forms containing sodium bicarbonate as an active ingredient 
would be allowed to make a claim for ``relief of overindulgence in food 
and drink.'' The proposed warnings would alert consumers to avoid 
antacid drug products containing sodium bicarbonate when the stomach is 
overly full from eating or drinking. The proposed directions would 
inform consumers that sodium bicarbonate should be completely dissolved 
before drinking and that the recommended dose should not be exceeded. 
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 June 4, 1974 (39 FR 19862), FDA issued a 
final monograph for OTC antacid drug products that established 
conditions in part 331 (21 CFR part 331) under which these drug 
products are generally recognized as safe and effective and not 
misbranded. Sodium bicarbonate is listed as a permitted active 
ingredient in Sec. 331.11. Permitted indications for products 
containing sodium bicarbonate are in Sec. 331.30 and include relief of 
the symptoms of ``heartburn,'' ``sour stomach,'' and/or ``acid 
indigestion.'' In the Federal Register of August 31, 1982 (47 FR 
38481), permitted indications for OTC antacid drug products were 
changed to the following: ``For the relief of'' (optional, any or all 
of the following:) ``heartburn,'' ``sour stomach,'' and/or ``acid 
indigestion'' (which may be followed by the optional statement:) ``and 
upset stomach associated with'' (optional, as appropriate) ``this 
symptom'' or ``these symptoms.'' The agency recognized that ``upset 
stomach'' is a general term used by consumers to describe symptoms 
associated with gastric hyperacidity such as acid indigestion, 
heartburn, or sour stomach (47 FR 38481 at 38482).
    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 46204 at 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) 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 the ingestion 
of sodium bicarbonate for the relief of gastrointestinal distress. 
These adverse effects include the possibility of stomach rupture and, 
in rare cases, death. (See discussion in section II of this document.) 
Based on a review of these reports of adverse effects, the agency is 
proposing labeling changes for OTC antacid drug products containing 
sodium bicarbonate as an active ingredient in dosage forms that are 
intended to be dissolved in liquid before administration. The agency 
considers these labeling changes necessary for the safe use of these 
products.
    Elsewhere in this issue of the Federal Register, the agency is also 
proposing to amend Sec. 343.60(b)(2) and (b)(4) of the internal 
analgesic tentative final monograph to include labeling indications, 
warnings, and directions specifically for internal analgesic/antacid 
combination products containing sodium bicarbonate as an active 
ingredient in a dosage form intended to be dissolved in liquid before 
administration.

II. Stomach Rupture Associated With Sodium Bicarbonate

    After reviewing the literature and the case reports, the agency 
concludes that the ingestion of sodium bicarbonate may, under certain 
circumstances, induce acute gastric dilatation (stretching of the 
stomach beyond normal dimensions) and rupture.Sodium bicarbonate reacts 
with gastric acid to form sodium chloride, water, and carbon dioxide. A 
rapid accumulation of carbon dioxide in the stomach may occur if sodium 
bicarbonate is ingested before it is fully dissolved (i.e., before all 
the gas has evolved) (Refs. 1 through 4). In this case, an individual 
may not have ingested a solution of sodium bicarbonate, but rather a 
suspension of sodium bicarbonate, that is, partially dissolved material 
with the complete dissolution likely to occur inside the stomach. As 
long as the effervescent reaction of sodium bicarbonate continues in 
the stomach, carbon dioxide is produced. The increased amount of carbon 
dioxide may induce gastric dilatation. If the stomach is overly full, 
such as after ingestion of a large meal, especially with large amounts 
of liquids, there is limited space for expansion and a rupture can 
occur (Refs. 1 through 4).

A. Summary of Literature Case Reports

    In 1986, Lazebnik, Iellin, and Michowitz (Ref. 5) reviewed eight 
cases of rupture of the normal stomach following ingestion of sodium 
bicarbonate. The cases had been reported from 1926 to 1986. Seven of 
these cases had previously been reported individually in the literature 
(Refs. 6 through 12). Six cases involved overindulgence in food and/or 
alcoholic beverages, while in two cases, no meal was ingested. However, 
in one case where no meal was ingested, the subject drank an entire 
bottle of citrate of magnesia prior to ingestion of sodium bicarbonate. 
Although in most cases the person took higher than recommended doses of 
the antacid, in some cases the person took smaller amounts. In some 
cases, it is not clear whether the sodium bicarbonate was taken 
directly without mixing with liquid or was taken as a solution or 
suspension. All of the people who experienced gastric rupture in 1963 
or earlier died. In the more recent cases, the people underwent repair 
of the ruptured stomach. Although serious complications, such as 
formation of abscesses, atelectasis, and gastric fistula occurred, in 
all of the cases occurring after 1963, the people survived.
    Brismar, Strandberg, and Wiklund (Ref. 13) reported a case of 
spontaneous stomach rupture after ingestion of sodium bicarbonate that 
took place in Sweden in 1986. A 43-year-old male consumed a large meal 
consisting of new potatoes, herring pickled in vinegar, and aerated 
water. At the end of this meal, the man ingested approximately 30 grams 
(g) of sodium bicarbonate. (The report does not describe the method of 
administration.) Immediately afterwards he experienced a rapidly 
increasing sensation of filling, with abdominal distention, very severe 
abdominal pain, and a sensation that something had ``burst'' in his 
abdomen. He was transported to the hospital and was found to have a 5-
centimeter (cm)-long rupture on the posterior aspect of his stomach 
close to the lesser curvature. The authors state that at the 
recommended dose of sodium bicarbonate, corresponding to approximately 
1.8 g, only 20 milliliters (mL) of gas is released within 3 minutes. 
However, if 8.4 g of sodium bicarbonate is added to the same volume of 
gastric juice (1,000 mL with a concentration of 100 milliequivalents 
(meq) per liter (L)), 470 mL of gas will be produced. The ingestion of 
30 g of sodium bicarbonate resulted in enormous gas development with 
resultant stomach rupture.
    In 1989, Downs and Stonebridge (Ref. 14) reported a case of stomach 
rupture in Scotland in which a 70-year-old man took 2 teaspoons (12 g) 
of sodium bicarbonate in water following a large meal. His abdomen 
rapidly distended, becoming tense and uncomfortable. He experienced 
increasing difficulty in breathing and could neither vomit nor belch. 
This was followed by a severe, sudden epigastric pain, as though 
``something had burst.'' A 6-cm tear on the anterior surface of the 
lesser curvature of the stomach had occurred. The authors estimated 
that the approximate volume of gas produced from the chemical reaction 
of 12 g of sodium bicarbonate is 3.4 L, approaching the 4 L estimate 
necessary to cause stomach rupture.

B. Summary of Case Reports

    The agency has identified a total of 29 cases of adverse effects 
associated with the ingestion of sodium bicarbonate for the relief of 
gastrointestinal distress. These cases were obtained from a search of 
the FDA Spontaneous Reporting System (SRS), a literature review, and 
voluntary submissions from a manufacturer covering the period from 1926 
to May 1993. Included in this total are 21 cases of stomach rupture. 
Death occurred in five of these cases. All of these case reports are on 
file in the Dockets Management Branch (Refs. 15 and 16). The agency's 
summary of these case reports follows.
    In August 1979 a 52-year-old male ate a large meal and consumed 
several alcoholic beverages. Shortly after going to bed, he awakened 
with indigestion. He then mixed a teaspoon of baking soda with a small 
amount of water, drank the mixture, and less than a minute later 
collapsed in agony because of sudden onset of severe abdominal pain. An 
exploratory laparotomy revealed a 6-cm tear in the stomach extending 
from the gastroesophageal junction down the lesser curvature of the 
stomach.
    In the second case report (June 1981), a 31-year-old male ingested 
a large Mexican meal, felt uncomfortable, put one dosage (amount 
unknown) of baking soda in a glass with water, and quickly drank the 
mixture. He immediately experienced severe, intense abdominal pain, 
could neither vomit nor belch, and his abdomen became markedly 
distended. Exploratory surgery revealed a 5-cm linear tear along the 
lesser curvature of the stomach.
    The third case report (April 1982) involved a 56-year-old female 
who had been on a liquid protein diet for 1 month prior to her 
hospitalization. She ate a large dinner accompanied by champagne and 
bicarbonate of soda. No information was provided on the amount of the 
dose or how it was taken. She was admitted to the hospital with acute 
abdominal pain, and exploratory laparotomy revealed a 12-cm tear 
extending from the distal esophagus onto the posterior aspect of the 
lesser curvature of the stomach. The size of the gastric tear was so 
big that it allowed the extrusion of gastric contents into the 
peritoneal cavity. It is conceivable that in this case the patient's 
stomach had been modified and even became atrophic because of the 
liquid diet and, thereby, sustained more damage as a consequence of the 
sodium bicarbonate-induced distention.
    The fourth case report (December 1983) involved a 37-year-old male 
who developed progressive abdominal pain after dinner. He drank soda 
with some sodium bicarbonate and then experienced severe chest and back 
pain, and shock. At laparotomy, a tear of the stomach just below the 
gastroesophageal juncture was found. In this case, the ingestion of 
soda and sodium bicarbonate may have aggravated the situation because 
soda is very acidic and produces carbon dioxide in addition to that 
produced by the sodium bicarbonate.
    The fifth case report (October 1984) involved a 42-year-old male 
with a history of slight burning epigastric pain an hour following 
heavy meals and exacerbated by strong foods such as onions, cabbages, 
and spicy foods. On the night of his admission to the hospital, he had 
eaten a large meal of hot, spiced chili and then promptly ingested two 
beers. He then ingested bicarbonate of soda and experienced a 
spontaneous onset of abdominal pain. An exploratory laparotomy revealed 
a perforation along the lesser curvature of the stomach. Initially, 
this case appeared to be one of a perforated gastric or duodenal ulcer, 
but during the ensuing operation and under subsequent microscopic 
examination, no ulcer was found.
    The sixth case report (December 1988) describes a 23-year-old male 
who had increasingly severe abdominal pain with subsequent vomiting 
after eating a spaghetti dinner. At some time the subject took sodium 
bicarbonate, but there was no information on how much was ingested, 
whether it was completely dissolved, how much water was taken with it, 
or exactly when it was taken. However, on exploratory laparotomy, a 6- 
to 7-cm linear tear in the lesser curvature of the stomach was found.
    The seventh report (June 1989) involved a 37-year-old male who 
experienced heartburn, for which he took a bismuth subsalicylate-
containing product. He then developed severe diffuse abdominal pain. On 
the trip to the emergency room, he stated that he had eaten a lot of 
food and had taken some baking soda when the pain became very severe. 
However, that statement is the only indication in the medical records 
that the subject ingested sodium bicarbonate prior to his injury. Thus, 
there is some question whether sodium bicarbonate ingestion actually 
occurred in this case.
    The eighth case report (July 1991) involved a 39-year-old male with 
no previous history of gastrointestinal disease. He had a large Mexican 
meal and developed epigastric distress for which he took some sodium 
bicarbonate. When his sleep was interrupted by continuing epigastric 
distress, he arose and took at least 2 tablespoons of sodium 
bicarbonate. (This amount is higher than the recommended dose.) Within 
2 minutes, he experienced an acute onset of severe epigastric pain. An 
exploratory laparotomy revealed a 4-cm perforation on the lesser 
curvature of the stomach. Neither the surgeon nor the pathologist could 
definitely document the presence of an ulcer. However, the patient did 
have a moderate narrowing of the pylorus due to mucosal scarring. 
Because this condition interfered with gastric emptying, it may have 
contributed to the reported problem.

C. Additional Data

    In December 1990, a probability sample survey was conducted to 
determine the number of doses of sodium bicarbonate taken by American 
adults annually to settle an upset stomach (Ref. 17). In this survey, 
20 percent of the U.S. adult population 18 years of age and older 
answered affirmatively when asked if they ever use baking soda or 
bicarbonate of soda to help settle an upset stomach. Based on an 
estimated adult population of 186.4 million, the survey indicated that 
37.3  6.5 million adults used sodium bicarbonate for an 
upset stomach. The average (mean) frequency with which these people use 
bicarbonate is 19.7 times during a 1-year period, which indicates that 
734.8 million doses of sodium bicarbonate are taken by American adults 
annually (S.D. 235.8 million). Further statistical analysis revealed 
that the median dose frequency was five times per year per user.
    An independent estimate of doses of sodium bicarbonate ingested per 
year calculated from the weight of consumer baking soda sold each year 
and the amount used by consumers for indigestion, as gauged by consumer 
surveys, was also provided to the agency (Ref. 18). Although not 
identical, the number of doses estimated, based on this information, is 
within the range of the survey discussed above. Regardless of the 
method of calculation used, the agency concludes that the number of 
doses-per-year of sodium bicarbonate is very large.
    The agency also considers the 21 identified cases of gastric 
rupture that have occurred in association with sodium bicarbonate to be 
a very serious but uncommon event. The agency is proposing changes in 
the labeling of OTC drug products containing sodium bicarbonate so that 
such products can be used safely and the incidence of untoward effects 
reduced to the lowest possible levels.

III. Additional Agency Concerns

    In addition to the serious adverse reactions described above, 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.
    Sodium bicarbonate is readily absorbed and may produce systemic 
metabolic alkalosis and/or sodium overload, particularly if taken in 
large doses or for a prolonged period of time. Rapid alkalization may 
precipitate tetany in people having hypocalcemia and cause 
cardiotoxicity and paralysis in people having hypokalemia (Refs. 1, 2, 
3, and 19 through 24). These occurrences can be life-threatening 
medical emergencies. The agency is aware of one death attributed to 
complications resulting from severe metabolic alkalosis caused by 
ingestion of sodium bicarbonate (Ref. 19). In this case, a 45-year-old 
man was admitted to an emergency room in alert and stable condition but 
complaining of burning pain in his arms and legs. He admitted taking 
baking soda for epigastric pain over the past several days. Although 
the total amount consumed was not ascertained, the man had a half empty 
8-ounce box of baking soda in his pocket. Shortly after admission, the 
man had a sudden, unexpected cardiopulmonary arrest. During this 
period, no medications were given (including sodium bicarbonate). A 
diagnosis of severe metabolic alkalosis was made after laboratory 
results revealed a primary elevation in serum bicarbonate 
concentration. The man remained comatose and died (due to infectious 
complications) 14 days after admission.
    Large doses or chronic administration of sodium bicarbonate with 
milk or calcium may lead to an increase in calcium absorption and may 
precipitate the milk-alkali syndrome. This syndrome is characterized by 
hypercalcemia, reduced secretion of parathyroid hormone, retention of 
phosphate, precipitation of calcium salts in the kidney, alkalosis, and 
renal insufficiency or failure. Symptoms include nausea, vomiting, 
headache, mental confusion, and anorexia. This may be particularly 
important in pregnancy where milk or calcium intake is emphasized 
(Refs. 1, 2, 3, and 25).
    Each g of sodium bicarbonate contains 12 meq of sodium. This large 
quantity may cause problems for people who are pregnant, on low-salt 
diets, receiving diuretics, or have a tendency toward fluid overload 
(Ref. 2). Even moderate amounts of sodium bicarbonate may expand plasma 
volume, increase blood pressure, and lead to edema (Ref. 1). The final 
monograph for OTC antacid drug products limits the daily dosage for 
sodium to 200 meq for persons up to 60 years old and to 100 meq for 
persons 60 years or older. Limitations for bicarbonate ion are also 200 
meq for persons up to 60 years old and 100 meq for persons 60 years or 
older. (See Sec. 331.11(b) and (k)(1).)
    Because of the potential severity of the adverse effects of sodium 
bicarbonate, the agency is concerned that the risk to consumers from 
ingestion of sodium bicarbonate in antacid doses may outweigh the 
benefit. There are many other OTC antacid ingredients currently 
available that do not pose the possibility of such serious side 
effects. Based on the concerns discussed above, the agency is 
considering the need for additional changes and/or additions to the 
indications and/or warnings provided for sodium bicarbonate in the 
antacid monograph (21 CFR part 331).
    For example, the agency has concerns how the presently allowed 
portion of the indications in Sec. 331.30(b) that mentions ``upset 
stomach'' may be confusing to consumers in light of the new warning 
being proposed in this document. The agency questions whether consumers 
will be able to recognize that sodium bicarbonate should not be used to 
relieve an ``upset stomach'' caused by excessive eating or drinking. 
The agency invites specific comment on how the indications for sodium 
bicarbonate antacid products might be changed and on any of the other 
issues discussed above or any additional issues that relate to the safe 
and effective use of sodium bicarbonate as an OTC antacid drug product. 
For example, the agency notes that a major manufacturer of baking soda 
currently voluntarily labels its product with warnings similar to those 
proposed in this document (Ref. 26).

References

    (1) Gennaro, A., editor, ``Remington's Pharmaceutical 
Sciences,'' 18th ed., Mack Publishing Co., Easton, PA, pp. 777-778 
and 819-820, 1990.
    (2) Garnett, W. R., ``Antacid Products''in ``Handbook of 
Nonprescription Drugs,''9th ed., American Pharmaceutical 
Association, Washington, p. 257, 1990.
    (3) Brunton, L. L., ``Agents for Control of Gastric Acidity and 
Treatment of Peptic Ulcers'' in ``The Pharmacological Basis of 
Therapeutics,'' 8th ed., edited by L. S. Goodman and A. G. Gilman, 
PergamonPress Co., Inc., New York, pp. 904-909, 1990.
     (4) Fordtran, J. S. et al., ``Gas Production After Reaction of 
Sodium Bicarbonate and Hydrochloric Acid,'' Gastroenterology, 
87:1014-1021, 1987.
    (5) Lazebnik, N., A. Iellin, and M. Michowitz, ``Spontaneous 
Rupture of the Normal Stomach After Sodium Bicarbonate Ingestion,'' 
Journal of Clinical Gastroenterology, 8(4):454-456, 1986.
    (6) Murdfield, P., ``Rupture of the Stomach from Sodium 
Bicarbonate,'' Journal of the American Medical Association, 87:1692 
-1693, 1926.
    (7) Lemmon, W. T., and G. W. Paschal, ``Rupture of the Stomach 
Following Ingestion of Sodium Bicarbonate,'' Annals of Surgery, 114: 
997-1003, 1941.
    (8) Burket, D. G., ``Spontaneous Rupture of the Stomach. Report 
of a Case,'' Journal of the American Medical Association, 139:27 -
28, 1949.
    (9) Kregel, L. A., ``Spontaneous Rupture of the Stomach,'' 
American Journal of Surgery, 21:505-507, 1955.
    (10) Bruno, M. S., W. R. Grier, and W. B. Ober, ``Spontaneous 
Laceration and Rupture of the Stomach,'' Archives of Internal 
Medicine, 112:574-583, 1963.
    (11) Zer, M. et al., ``Spontaneous Rupture of the Stomach 
Following Ingestion of Sodium Bicarbonate,'' Archives of 
Surgery,101:532-533, 1970.
    (12) Mastrangelo, M. R., and E. W. Moore,``Spontaneous Rupture 
of the Stomach in a Healthy Adult Man After Sodium Bicarbonate 
Ingestion,'' Annals of Internal Medicine, 101:649-650, 1984.
    (13) Brismar, B., A. Strandberg, and B. Wiklund, ``Stomach 
Rupture Following Ingestion of Sodium Bicarbonate,'' Acta Chirurgica 
Scandinavica, 530:97-99, 1986.
    (14) Downs, N. M., and P. A. Stonebridge,``Gastric Rupture Due 
to Excessive SodiumBicarbonate Ingestion,'' Scottish Medical 
Journal, 34:534-535, 1989.
    (15) Medical records submitted by Church & Dwight Co., Inc., 
included in OTC Vol. 01AM2, Docket No. 93N-0164, Dockets Management 
Branch.
    (16) Memorandum from M. Chen, FDA, to W. Gilbertson, FDA, dated 
December 1, 1991, in OTC Vol. 01AM2, Docket No. 93N-0164, Dockets 
Management Branch.
    (17) Survey Center, Inc., ``Use of Soda Bicarbonate to Settle an 
Upset Stomach,'' draft of unpublished consumer survey in OTC Vol. 
01AM2, Docket No. 93N-0164, Dockets Management Branch.
    (18) Letter from W. Sorenson, Church & Dwight Co., Inc., to H. 
Gallo-Torres, FDA, dated April 23, 1992, copy included in OTC Vol. 
01AM2, Docket No. 93N-0164, Dockets Management Branch.
    (19) Mennen, M., and C. Slovis, ``Severe Metabolic Alkalosis in 
the Emergency Department,'' Annals of Emergency Medicine, 17:4:354-
357, 1988.
    (20) Brown, A. L., S. Whaley, and W. Arnold, ``Acute Bicarbonate 
Intoxication From a Folk Remedy,'' American Journal of Diseases of 
Children, 135:965, 1981. (21) Robertson, W. O., ``Baking Soda 
(NaHCO3) Poisoning,'' Veterinary and Human Toxicology, 30(2):164-
165, 1988.
     (22) Wechsler, D., L. Ibsen, and P. Fosarelli, ``Apparent 
Proteinuria as a Consequence of Sodium Bicarbonate 
Ingestion,''Pediatrics, 86(2):318-319, 1990.(23) Linford, S. M., and 
H. D. James, ``Sodium Bicarbonate Abuse: A Case Report,''British 
Journal of Psychiatry, 149:502-503, 1986.
    (24) ``Drug Evaluations,'' 6th ed., American Medical 
Association, Chicago, p. 833, 1986.
    (25) ``Drug Evaluations Subscription,''Vol. 2, American Medical 
Association, Chicago, p.1-18, Spring 1990.
    (26) Copy of labeling for Arm & Hammer Baking Soda in OTC Vol. 
01AM2, Docket No. 93N-0164, Dockets Management Branch.

IV. The Agency's Proposal for Revised Labeling for Sodium 
Bicarbonate in OTC Antacid 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, e.g., powders or 
effervescent granules or tablets. In some cases, the person drank a 
solution or suspension of sodium bicarbonate, while in other cases the 
person ingested the sodium bicarbonate in a dry form. The agency is 
aware of OTC antacid drug products in chewable tablet dosage form, in 
which sodium bicarbonate is an inactive ingredient. However, the agency 
is not aware of any reports of gastric dilatation and stomach rupture 
resulting from ingestion of these products. Accordingly, the agency is 
proposing to amend Sec. 331.30 to include specific indication, warning, 
and direction statements for all OTC antacid drug products containing 
sodium bicarbonate as an active ingredient in dosage forms intended to 
be dissolved in liquid before administration. Separate indications are 
proposed in Sec. 331.30(b) for products that either do or do not 
contain sodium bicarbonate as an active ingredient intended to be 
dissolved in liquid before administration. Antacid products containing 
sodium bicarbonate as an active ingredient will not be allowed to 
include a claim for relief of overindulgence in food and drink. In 
addition, the agency is proposing that these sodium bicarbonate 
products bear new warnings and directions.
    Because of the potential serious health risk involved, the agency 
is proposing that the new warnings appear after the header ``STOMACH 
WARNING.'' Portions of the new warnings must appear in bold print and 
in capital letters. The proposed warnings read as follows:
    ``To avoid serious injury, do not take until'' (insert product 
dosage form, e.g., ``tablet,'' ``powder'') ``is completely 
dissolved. It is very important not to take this product when overly 
full from food or drink. [first two sentences in boldface type and 
all capital letters] Consult a doctor if severe stomach pain occurs 
after taking this product.''
    Additional directions, proposed to appear after the header 
``DIRECTIONS,'' read as follows:
    ``Dissolve completely in water'' [For effervescent dosage forms 
add: ``and be sure all bubbling has stopped''] ``before drinking. Do 
not exceed recommended dose. [second sentence in boldface type and 
all capital letters] See Warnings.''
    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 antacid drug 
products containing sodium bicarbonate as an 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. Further, a major 
manufacturer of baking soda currently voluntarily labels its product 
with statements similar to those proposed in this amendment. 
Manufacturers will have 6 months after the date of publication of the 
final rule in which to implement this relabeling. However, 
manufacturers of OTC antacid 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 a 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 
antacid drug products. 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 antacid 
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 331

    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 331 be amended as follows:

PART 331--ANTACID PRODUCTS FOR OVER-THE-COUNTER (OTC) HUMAN USE

    1. The authority citation for 21 CFR part 331 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).
    2. Section 331.30 is amended by revising paragraph (b), and by 
adding new paragraphs (c)(8), (e)(1), and (e)(2) to read as follows:

Sec. 331.30   Labeling of antacid products.

* * * * *
    (b)  Indications. The labeling of the product states under the 
heading ``Indications,'' any of the phrases listed in this paragraph, 
as appropriate. Other truthful and nonmisleading statements, describing 
only the indications for use that have been established and listed in 
this paragraph, may also be used, as provided in Sec. 330.1(c)(2) of 
this chapter, subject to the provisions of section 502 of the Federal 
Food, Drug, and Cosmetic Act (the act) relating to misbranding and the 
prohibition in section 301(d) of the act against the introduction or 
delivery for introduction into interstate commerce of unapproved new 
drugs in violation of section 505(a) of the act.
    (1) For products containing active ingredients identified in 
Sec. 331.11(a) through (j), (k)(2), (l), and (m). ``For the relief of'' 
(select any or all of the following: ``heartburn,'' ``sour stomach,'' 
and/or ``acid indigestion'') which may be followed by the statement: 
``and upset stomach associated with'' (select one or more of the 
following, as appropriate: ``this symptom,'' ``these symptoms,'' or 
``overindulgence in food and drink.''))
    (2) For products containing sodium bicarbonate as an active 
ingredient in a dosage form intended to be dissolved in liquid before 
administration identified in Sec. 331.11(k)(1). ``For the relief of'' 
(select any or all of the following: ``heartburn,'' ``sour stomach,'' 
and/or ``acid indigestion'') (which may be followed by the statement: 
``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.''
    (c) *  *  *
    (8) For products containing sodium bicarbonate as an active 
ingredient in a dosage form intended to be dissolved in liquid before 
administration identified in Sec. 331.11(k)(1), portions of the warning 
statements must appear in bold print and in capital letters as follows: 
``STOMACH WARNING: To avoid serious injury, do not take until'' (insert 
product dosage form, e.g., ``tablet,'' ``powder'') ``is completely 
dissolved. It is very important not to take this product when overly 
full from food or drink. [first two sentences in bold print and all 
capital letters] Consult a doctor if severe stomach pain occurs after 
taking this product.''
* * * * *
    (e) *  *  *
    (1) The labeling for products containing sodium bicarbonate as an 
active ingredient in a dosage form intended to be dissolved in liquid 
before administration identified in Sec. 331.11(k)(1) contains the 
following additional directions: ``Dissolve completely in water'' [For 
effervescent dosage forms add: ``and be sure bubbling has stopped''] 
``before drinking. Do not exceed recommended dose. [second sentence in 
bold print and all capital letters] See Warnings.''(2) [Reserved]
* * * * *

    Dated: November 3, 1993.
Michael R. Taylor,
Deputy Commissioner for Policy.
[FR Doc. 94-2264 Filed 2-1-94; 8:45 am]
BILLING CODE 4160-01-F