Antacid Drug Products for Over-the-Counter Human Use; Proposed Amendment of Antacid Final Monograph

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