[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]
_______________________________________________________________________
Part VI
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
21 CFR Part 331
Antacid Drug Products for Over-the-
Counter Human Use; Amendment to Antacid Final Monograph; Proposed Rule
=======================================================================
-----------------------------------------------------------------------
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.
-----------------------------------------------------------------------
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