[Federal Register Volume 63, Number 98 (Thursday, May 21, 1998)]
[Rules and Regulations]
[Pages 27836-27844]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-12053]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 201
[Docket No. 78N-036L]
RIN 0910-AA01
Package Size Limitation for Sodium Phosphates Oral Solution and
Warning and Direction Statements for Oral and Rectal Sodium Phosphates
for Over-the-Counter Laxative Use
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule
to limit the container size for sodium phosphates oral solution
(dibasic sodium phosphate/monobasic sodium phosphate oral solution) to
not greater than 90 milliliters (mL) (3 ounces (oz)) when used as an
over-the-counter (OTC) laxative drug product. FDA is limiting the
container size because of reports of deaths associated with an
overdosage of sodium phosphates oral solution when the product was
packaged in a larger-size container and a larger than intended dose was
ingested inadvertently. The agency is also requiring warning and
direction statements to inform consumers that exceeding the recommended
dose of oral and rectal sodium phosphates products in a 24-hour period
can be harmful. This final rule is part of the ongoing review of OTC
drug products conducted by FDA.
DATES: The regulation is effective June 22, 1998, however compliance
with
[[Page 27837]]
Sec. 201.307(b)(2) and (b)(3) is not mandatory until September 18,
1998.
FOR FURTHER INFORMATION CONTACT: Cheryl A. Turner, Center for Drug
Evaluation and Research (HFD-560), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-827-2222.
SUPPLEMENTARY INFORMATION:
I. Background
In the Federal Register of March 21, 1975 (40 FR 12902), FDA
published, under Sec. 330.10(a)(6) (21 CFR 330.10(a)(6)), an advance
notice of proposed rulemaking to establish a monograph for OTC
laxative, antidiarrheal, emetic, and antiemetic drug products, together
with the recommendations of the Advisory Review Panel on OTC Laxative,
Antidiarrheal, Emetic, and Antiemetic Drug Products (the Panel), which
was the Advisory Review Panel responsible for evaluating data on the
active ingredients in these classes. The Panel recommended monograph
status for phosphate salts, such as sodium phosphates oral solution (40
FR 12902 at 12940), but did not recommend any container size
limitations.
The agency's proposed regulation, in the form of a tentative final
monograph, for OTC laxative drug products was published in the Federal
Register of January 15, 1985 (50 FR 2124). The agency also proposed
monograph status for sodium phosphates oral solution (50 FR 2124 at
2152 and 2155), but did not recommend any container size limitations.
The agency proposed the following dosage for sodium phosphates oral
solution for adults and children 12 years of age and over: 3.42 to 7.56
grams (g) of dibasic sodium phosphate and 9.1 to 20.2 g of monobasic
sodium phosphate \1\ in a single daily dose. (See proposed
Sec. 334.58(d)(5)(i) (21 CFR 334.58(d)(5)(i)), 50 FR 2124 at 2155.) In
addition to its use as an OTC laxative for the relief of occasional
constipation, sodium phosphates oral solution \2\ is used as part of a
bowel cleansing regimen in preparing a patient for surgery or for
preparing the colon for x-ray or endoscopic examination. (See proposed
Sec. 334.80(a)(2), 50 FR 2124 at 2157.) Sodium phosphates oral solution
and sodium phosphates enema \3\, respectively, are the current United
States Pharmacopeia (USP) names for the oral and rectal dosage forms of
the combination of sodium phosphates ingredients.
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\1\ In the tentative final monograph for OTC laxative drug
products, published in the Federal Register of January 15, 1985 (50
FR 2124), and in the proposed rule for package size limitation for
OTC laxative drug products published in the Federal Register of
March 31, 1994 (59 FR 15139), the agency referred to dibasic sodium
phosphate as ``sodium phosphate,'' and monobasic sodium phosphate as
``sodium biphosphate.'' The current nomenclature in the USP
Dictionary of USAN and International Drug Names, 1997 is ``dibasic
sodium phosphate'' and ``monobasic sodium phosphate,'' respectively.
This final rule uses the current nomenclature.
\2\Sodium phosphates oral solution is the official name for a
solution of dibasic sodium phosphate and monobasic sodium phosphate
in the U.S. Pharmacopeia 23/National Formulary 18, 1995.
\3\ Sodium phosphates enema is the official name for a solution
of dibasic sodium phosphate and monobasic sodium phosphate in the
U.S. Pharmacopeia 23/National Formulary 18, 1995.
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In the Federal Register of March 31, 1994 (59 FR 15139), the agency
proposed to amend the tentative final monograph for OTC laxative drug
products to limit the OTC container size for sodium phosphates oral
solution to not greater than 90 mL. The agency also proposed a warning
for all oral and rectal dosage forms of sodium phosphates products to
inform consumers not to exceed the recommended dosage unless directed
by a doctor. Interested persons were invited to submit written comments
on the proposed regulation and on the agency's economic impact
determination by May 31, 1994.
In response to the proposal, two manufacturers of laxative drug
products submitted comments. Neither comment addressed the agency's
economic impact determination. Copies of these comments are on public
display in the Dockets Management Branch (HFA-305), Food and Drug
Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857.
Additional information that has come to the agency's attention since
publication of the proposal is also on public display in the Dockets
Management Branch.
In the proposal, the agency discussed its reasons for limiting the
package size for sodium phosphates oral solution (59 FR 15139). The
agency noted that the major trade product containing sodium phosphates
oral solution was marketed in 45-mL, 90-mL, and 240-mL bottles. The
purgative dose or dose used for colonoscopy is 45 mL. Because the
product was available in three sizes, the manufacturer's labeling
advised physicians to prescribe by volumes and not to prescribe by the
bottle and not to exceed the recommended dosage, as serious side
effects may occur. Despite this labeling, the multiple container sizes
available in the marketplace have caused consumer confusion and appear
to have been involved in several consumer deaths.
The agency determined that the OTC availability of the 240-mL
container of sodium phosphates oral solution creates a potential safety
risk, particularly for elderly persons who are likely to use the
product for bowel cleansing prior to surgery or a diagnostic procedure
involving the colon. Because of the reported cases of accidental
overdosing and the confusion that has occurred between 240-mL and 90-mL
container sizes, the agency proposed that the 240-mL size container of
sodium phosphates oral solution should no longer remain in the OTC
marketplace. In the interest of safety, the agency proposed to limit
the maximum OTC container size for this product to 90 mL.
The agency proposed to include the package size limitation and
warning in the monograph for OTC laxative drug products. However, that
monograph has not been finalized to date. Because of the potential
safety risk involved, the agency has decided to finalize both the
package size limitation and several new warning and direction
statements prior to completion of the final monograph for OTC laxative
drug products. The agency has decided to include this information in
part 201 (21 CFR part 201) at this time and to incorporate it into the
final monograph for OTC laxative drug products at a later date.
In the Federal Register of February 27, 1997 (62 FR 9024), FDA
proposed to establish a standardized format for the labeling of OTC
drug products. Until the proposal is finalized, manufacturers,
distributors, and packagers must comply with the final rule published
herein and all other currently applicable labeling regulations. The
agency will eventually use the final labeling rule to incorporate the
information included herein in part 201 into the final monograph for
OTC laxative drug products.
II. The Agency's Conclusions on the Comments
1. One comment stated that, according to the USP 22 (Ref. 1), the
current terminology for sodium phosphate is monobasic sodium phosphate
and for sodium biphosphate it is dibasic sodium phosphate. The comment
stated that the tentative final monograph should be amended
accordingly.
Under agency regulations in 21 CFR 299.4(e), the established name
of a drug is the current compendial name or the USAN (U.S. Adopted
Names Council) adopted name listed in the USP Dictionary of USAN and
International Drug Names. Both the U.S. Pharmacopeia 23/National
Formulary 18 (Ref. 2) and the USP Dictionary of USAN and International
Drug Names, 1997 (Ref. 3) list the current name for sodium phosphate as
``dibasic sodium phosphate,'' and for sodium
[[Page 27838]]
biphosphate as ``monobasic sodium phosphate.'' (See footnote 1, supra.)
It appears that the comment inadvertently reversed the names of the
ingredients.
2. One comment stated that the agency's proposal that the final
rule be effective 30 days after its publication in the Federal Register
is insufficient time. The comment argued that 30 days would not be
enough time for relabeling of its sodium phosphates products and
requested that the final rule be effective 120 days after its
publication in the Federal Register.
The agency is instituting a split effective date for this final
rule. Because of the potential serious safety risk involved, the agency
has determined that initial introduction or initial delivery for
introduction into interstate commerce of any container size of sodium
phosphates oral solution greater than 90 mL should cease as soon as
possible (within 30 days of this final rule). However, the agency
concurs with the comment that manufacturers need more than 30 days to
relabel these drug products and is granting the 120 days requested by
the comment. Because of the potential serious safety risks, the agency
has determined that manufacturers need to work promptly to relabel
their products. The agency is providing manufacturers the option to use
supplementary labeling (e.g., stick-on labeling) to add the new warning
and direction information to currently manufactured products not yet
introduced into interstate commerce or on package labeling that has not
yet been incorporated into the manufacturing process. If manufacturers
choose not to use stick-on labeling, they are encouraged to have new
labeling containing the new warning and direction information printed
as expeditiously as possible in the interest of safe use of these
products.
3. One comment stated that sodium phosphates oral solution should
not be marketed in packages containing more than 45 mL. The comment
argued that 45 mL of this product equals the ``single daily dose'' of
solution generally recognized as safe and effective for use as a
laxative and bowel cleansing agent in the tentative final monograph.
The comment provided data to show that taking more than this amount has
been shown to cause significant changes in blood levels of sodium,
potassium, phosphate, chloride, and calcium, thereby imposing a risk of
serious injury (Refs. 4, 5, and 6).
The agency does not agree with the comment that packages containing
more than 45 mL of sodium phosphates oral solution should not be
marketed. Problems that previously occurred involved confusion
resulting from the availability of a 240-mL container size (59 FR
15139). (In 1993, the manufacturer of the major trade product
containing this solution ceased manufacture and initiated a market
withdrawal of the 240-mL container size.) The oral solution is
currently marketed in 45-mL and 90-mL containers. The agency has not
received any reports that a one-time 90 mL dose has resulted in a death
or a serious adverse reaction requiring medical treatment.
The agency has reviewed the submitted data (Refs. 4, 5, and 6) and
agrees that taking more than 45 mL of sodium phosphates solution over a
10- to 12-hour period can result in significant changes in electrolytes
and may impose a risk of serious injury. (See comment 4 in section II
of this document.) Therefore, the agency is requiring specific warning
and direction statements to ensure that the correct dose is used and
that consumers do not use more than the recommended dose in a 24-hour
period. The agency proposed to amend the tentative final monograph for
OTC laxative drug products to include in Sec. 334.58(c)(2)(iv) the
following warning for oral and rectal dosage forms of sodium phosphates
products: ``Do not exceed recommended dose unless directed by a doctor.
Serious side effects many occur from excess dosage'' (59 FR 15139).
In this final rule, the agency is revising the proposed warning by
adding 24-hour dosing information and by simplifying the language. The
agency is also requiring separate warnings for oral and rectal enema
drug products. For oral sodium phosphates drug products, the new
warning states: ``Taking more than the recommended dose in 24 hours can
be harmful.'' For rectal sodium phosphates drug products, the new
warning states: ``Using more than one enema in 24 hours can be
harmful.'' Both warnings must be in boldface type and appear as the
first statement under the heading ``Warnings.'' (See comment 5 in
section II of this document.)
The agency is also adding new directions in boldface type
immediately preceding the dosage information, which state: ``Do not''
(``take'' or ``use'') ``more unless directed by a doctor. See
Warnings.'' (See comment 4 in section II of this document.) The new
directions appear in Sec. 201.307(b)(3)(i).
The agency notes that sodium phosphates oral solution is available
for general laxative use for relief of occasional constipation at a
single daily dose of 20 mL to 45 mL for adults and children 12 years of
age and over. Thus, a larger size container (90 mL) may be more
convenient for consumers to purchase and have available for future use.
The agency is also aware that the 45-mL and 90-mL container sizes are
often recommended and prescribed by physicians for bowel cleansing
prior to surgery and diagnostic procedures of the colon. Accordingly,
the agency is allowing the 90-mL container of sodium phosphates oral
solution to remain on the OTC market. However, in an effort to prevent
consumers from taking an entire 90-mL container in 1 day (24 hours),
the agency is adding additional statements in the directions in
Sec. 201.307(b)(3)(ii) to inform consumers how much of the oral
solution may be taken as a single daily dose and not to take more than
the recommended daily dose in a 24-hour period. The agency has also
revised the format for stating children's ages from that proposed in
Sec. 334.58(d)(5)(i) of the tentative final monograph (50 FR 2124 at
2155). The directions now state:
Adults and children 12 years of age and over: Oral dosage is
dibasic sodium phosphate 3.42 to 7.56 grams (g) and monobasic sodium
phosphate 9.1 to 20.2 g (20 to 45 mL dibasic sodium phosphate/
monobasic sodium phosphate oral solution) as a single daily dose.
``Do not take more than 45 mL (9 teaspoonfuls or 3 tablespoonfuls)
in a 24-hour period.''
Children 10 and 11 years of age: Oral dosage is dibasic sodium
phosphate 1.71 to 3.78 g and monobasic sodium phosphate 4.5 to 10.1
g (10 to 20 mL dibasic sodium phosphate/monobasic sodium phosphate
oral solution) as a single daily dose. ``Do not take more than 20 mL
(4 teaspoonfuls) in a 24-hour period.''
Children 5 to 9 years of age: Oral dosage is dibasic sodium
phosphate 0.86 to 1.89 g and monobasic sodium phosphate 2.2 to 5.05
g (5 to 10 mL dibasic sodium phosphate/monobasic sodium phosphate
oral solution) as a single daily dose. ``Do not take more than 10 mL
(2 teaspoonfuls) in a 24-hour period.'' Children under 5 years of
age: ask a doctor.
The agency notes that the directions for sodium phosphates oral
solution contain separate dosages for children 10 and 11 years of age
and for children 5 to 9 years of age. These age ranges are not
consistent with age ranges used for the majority of OTC laxative drug
products, which recommend dosages for children 6 to 11 years of age.
Therefore, elsewhere, in this issue of the Federal Register, the agency
is proposing to revise the directions for sodium phosphates oral
solution to limit the OTC use of these products to children 6 years of
age and above.
The proposed directions state:
* * * Children 6 to 9 years of age: Oral dosage is dibasic
sodium phosphate 0.86 to 1.89 g and monobasic sodium phosphate 2.2
to 5.05 g (5 to 10 mL dibasic sodium phosphate/monobasic sodium
phosphate oral
[[Page 27839]]
solution) as a single daily dose. `Do not take more than 10 mL (2
teaspoonfuls) in a 24-hour period.' Children under 6 years of age:
ask a doctor.
4. One comment requested that sodium phosphates oral solution
products bear a warning against consuming more than 45 mL in a 24-hour
period unless directed by a physician. The comment contended that there
are potentially serious health problems associated with high doses of
this product. The comment submitted data to show that consuming more
that 45 mL of sodium phosphates oral solution in 24 hours has resulted
in significant changes in blood levels of sodium, potassium, phosphate,
chloride, and calcium, thereby imposing a risk of serious injury (Refs.
4, 5, and 6).
The agency has reviewed the submitted data and agrees that
ingesting more that 45 mL of sodium phosphates oral solution in a 24-
hour period may be harmful. Clarkston et al. (Ref. 4) compared a
polyethylene glycol (PEG) based gastrointestinal lavage to a sodium
phosphates oral regimen. In this randomized trial, 26 subjects took 4
liters (L) of the PEG solution and 25 subjects took two 45-mL doses of
sodium phosphates oral solution 11 hours apart. The subjects had a
chemistry panel and ionized calcium done prior to taking the drug and
on the morning of the colonoscopy. The results indicated that the
sodium phosphates solution caused a decrease in ionized serum calcium
and serum potassium, with concomitant increases in phosphate. The
investigators stated that the sodium phosphates oral regimen resulted
in statistically significant changes in serum sodium, potassium,
phosphorus, and calcium (p < 0.01). The investigators concluded that
the risk of symptoms of hypocalcemia must be considered due to the
abnormal low levels of ionized calcium that frequently occur with this
regimen.
Vanner et al. (Ref. 5) compared a standard PEG based
gastrointestinal solution to a sodium phosphates oral solution prior to
colonoscopy. In this parallel, single-blinded, randomized study, 54
subjects received two 45-mL doses of the sodium phosphates oral
solution 11 hours apart, and 48 subjects received 4 L of the PEG
solution. The subjects had blood tests on admission and the morning of
the procedure. The authors concluded that the sodium phosphates oral
solution was safe and effective because serial measurements of blood
tests, postural pulse, and blood pressure changes did not reveal any
clinically significant changes in intravascular volume. One ``syncopal
episode'' occurred in the sodium phosphates group. The authors
mentioned that the subject's vital signs did not appear to indicate
that hypovolemia (abnormally decreased volume of circulating plasma)
was the cause. The authors reported that hyperphosphatemia occurred
with sodium phosphates, but serum phosphate values returned to normal
within 24 hours, and no concomitant decrease in calcium was seen. They
added that histological assessment for possible preparation-induced
changes revealed no difference between the two drugs.
The agency notes that numerous induced electrolyte abnormalities
occurred in this study. The data showed statistically significant
decreases in potassium and increases in hematocrit, sodium, chloride,
osmolality, and phosphate. Extreme serum phosphate levels reached 11.6
milligrams/deciliter (mg/dL) in the sodium phosphates group and 4.7 mg/
dL in the PEG group; normal values are 2.5 to 4.1 mg/dL. In
hyperphosphatemia, excessive complexing of calcium with phosphate may
contribute to a decrease in plasma ionized calcium, which results in
hypocalcemia. Calcium levels were not reported for the entire sodium
phosphates group nor was the risk of hypokalemia mentioned. The agency
notes that the postural changes in pulse, systolic blood pressure, and
the one ``syncopal episode'' were most likely due to decreased
intravascular volume in subjects in the sodium phosphates group.
Because elevated phosphate levels are known to occur with sodium
phosphates use, 15 subjects were randomly selected to have serum
phosphate and calcium levels measured at 4 p.m. on the day of
colonoscopy and at 8 a.m. the following day. Seven of the fifteen
subjects received the sodium phosphates regimen. Vanner et al. reported
that 2 hours after the second dose, the mean serum phosphorus was 7.2
mg/dL (nearly twice the pre-study value of 3.7 mg/dL), while the total
calcium values continued to decline for at least 24 hours after the
dose was taken.
The agency believes that the Vanner et al. study showed that
postural increases in pulse, decreases in systolic blood pressure, and
serum electrolyte and plasma volume shifts were greater in the sodium
phosphates group than in the PEG group. The incidence of postural
elevation in heart rate, indicating significant reduction in
intravascular volume, was also three times higher in the sodium
phosphates group than in the PEG group. Because of the small sample
size, the fact that none of the study subjects died or had serious side
effects that required hospitalization cannot be interpreted to mean
that two 45-mL doses of sodium phosphates oral solution are safe to
ingest without a physician's supervision.
Warner and DiPalma (Ref. 6) stated that sodium phosphates oral
solution is extremely popular for use as a bowel cleansing agent
because it is effective, easy to administer, and well tolerated.
However, they contended that little data are available concerning its
safety. They mentioned that the majority of trials evaluating the
product for use as a bowel cleanser have not systematically monitored
electrolytes. They asserted that the solubility product of calcium and
phosphate, when exceeded, leads to soft tissue calcification in areas
where an alkaline internal environment enhances calcium phosphate salt
deposit, primarily in the kidneys, heart, blood vessel, cornea, lungs,
and gastric mucosa. They stated that the normal calcium-phosphate
product is 40 mg/dL, which is tightly regulated through absorption,
excretion, and intracellular/extracellular ion shifts; and that the in
vitro solubility product of calcium is 58 mg/dL, well above the normal
value (Ref. 6). Warner and DiPalma mentioned that Vanner et al. (Ref.
5) and Kolts (Ref. 7) have presented limited data to show phosphate
levels rising to as high as 7 mg/dL with relatively unchanged serum
calcium values. According to Warner and DiPalma, the increase in
phosphate levels appeared quite transient, but because sampling was so
infrequent, it is impossible to ascertain whether even these high
values represent the peak phosphate concentrations after administration
of sodium phosphates oral solution.
Kolts (Ref. 8) responded to Warner and DiPalma, and argued that
sodium phosphates oral solution should be the preparation of choice for
most endoscopy outpatients due to its low cost, comfort for the
patient, and low incidence of adverse side events. Kolts stated that
the sodium phosphates oral solution used in his study (Ref. 7) had been
sold OTC for more than 100 years and the manufacturer had not reported
any serious side effects, except when the solution was taken in massive
overdoses or if used when contraindicated. Kolts added that there were
no reports of adverse events such as ectopic calcification in the
literature from 1966 to 1993 from the use of phosphate catharsis in
people with normal renal function. Kolts concluded that his (Ref. 7)
and Vanner's (Ref. 5) studies documented the minor changes
[[Page 27840]]
in clinically relevant electrolytes as well as the lack of adverse
symptoms from sodium phosphates oral solution.
The agency finds that the data show that sodium phosphates oral
solution can cause alterations in serum levels of sodium, potassium,
phosphate, chloride, and calcium. In some people, such changes can be
life-threatening. The agency has particular concerns about hypocalcemia
occurring due to its reported frequency when two 45-mL doses of sodium
phosphates oral solution are given over a 24-hour period. The reduction
of calcium levels reflects changes in ionized calcium (Ref. 9).
Hypocalcemia with subsequent low levels of ionized calcium may result
in neuromuscular irritability, heart block, and cardiovascular failure
(Ref. 9).
In the tentative final monograph for OTC laxative drug products (50
FR 2124 at 2155), the agency proposed a maximum single daily oral dose
of 7.56 g of dibasic sodium phosphate and 20.2 g of monobasic sodium
phosphate. The major manufacturer of sodium phosphates products
recommends (as part of a bowel cleansing regimen in preparation for
surgery or preparation of the colon for x-ray or endoscopic
examination) (Ref. 10) that 45 mL be given at 7 p.m. and again at 6
a.m. the following morning. The agency notes that 0.9 g/5 mL of dibasic
sodium phosphate is equivalent to 17.1 to 18.9 g/100 mL of sodium
phosphates oral solution, and that 2.4 g/5 mL of monobasic sodium
phosphate is equivalent to 45.6 to 50.4 g/100 mL of sodium phosphates
oral solution according to the USP 23 (Ref. 2). Therefore, over an 11-
hour period, 90 mL of solution (approximately 16.2 g of dibasic sodium
phosphate and 43.2 g of monobasic sodium phosphate) containing 9.9 g of
sodium could be consumed. The manufacturer of this product has not
submitted sufficient data to demonstrate the safety of more than 45 mL
of this solution in a 24-hour period (Ref. 11). Thus, the agency
concludes that the safe oral use of more than 7.56 g of dibasic sodium
phosphate and 20.2 g of monobasic sodium phosphate in a 24-hour period
has not been demonstrated at this time. Therefore, the agency will not
include a greater dosage in a 24-hour period in the OTC or professional
labeling in the final monograph for OTC laxative drug products, which
will be published in a future issue of the Federal Register.
The agency agrees with the comment that the labeling for sodium
phosphates oral solution should include a warning not to ingest more
than the recommended dose in a 24-hour period. Accordingly, the agency
is including the following warning in Sec. 201.307(b)(2)(i) for oral
products that contain sodium phosphates: ``Taking more than the
recommended dose in 24 hours can be harmful.'' The sentence is required
to appear in boldface type as the first statement under the heading
``Warnings.'' The agency is also requiring in Sec. 201.307(b)(3)(i)
that the directions for oral and rectal sodium phosphates products
contain the following statements in boldface type immediately preceding
the dosage information: ``Do not'' (``take'' or ``use'') ``more unless
directed by a doctor. See Warnings.'' (See comment 5 in section II of
this document.) These additional statements are intended to refer
consumers to the warnings when they read the directions for the
product.
5. One comment disagreed with the proposed warning in
Sec. 334.58(c)(2)(iv) for rectal enema sodium phosphates drug products,
which states: ``Do not exceed recommended dose unless directed by a
doctor. Serious side effects may occur from excess dosage.'' The
comment argued that the agency provided no concrete or specific
evidence to support this warning. The comment stated that its sodium
phosphates enema contains 19 g/118 mL (equivalent to 16 g/100 mL) of
monobasic sodium phosphate and 7 g/118 mL (equivalent to 7 g/100 mL) of
dibasic sodium phosphate. In contrast, the oral product contains 2.4 g/
5 mL (equivalent to 48 g/100 mL) of monobasic sodium phosphate and 0.9
g/5 mL (equivalent to 18 g/100 mL) of dibasic sodium phosphate. The
comment stated that because the phosphate concentration of the enema is
only one-third that of the oral product, use of the enema is not likely
to result in overdosage. The comment added that an overdosage is
unlikely to occur due to the way enemas are used and the results they
produce. The comment mentioned that the enema product is clearly
labeled ``Not intended for oral consumption,'' and that the current
labeling clearly states the appropriate dosage. Thus, the comment
concluded that the warning should not be required for sodium phosphates
enema products. Another comment stated that the dosage and
administration section of products containing sodium phosphates should
be allowed to contain statements similar to the following proposed
warning: ``Do not exceed recommended dose unless directed by a doctor.
Serious side effects may occur from excess dosage.'' The comment
indicated that such statements should be allowed, but do not need to be
included in the final rule.
The agency notes that the first comment made an error in its
statement of the amount of dibasic sodium phosphate per 100 mL. It
should have been approximately 6 g/mL which is consistent with USP 23
(Ref. 2), which states that each 100 mL of sodium phosphates enema
solution contains not less than 5.7 g and not more than 6.3 g of
dibasic sodium phosphate.
The agency is aware of numerous reports of misuse of sodium
phosphates enemas that resulted in adverse effects (Refs. 12 through
23). Wason et al. (Ref. 12) reported the case of a normal 5-month-old
child who was given an entire adult sodium phosphates enema by her
mother. Within 30 minutes, the child became extremely ill;
consciousness decreased; and shock, hyperphosphatemia, hypocalcemia,
and acidosis developed. The child was hospitalized and responded to
intravenous (IV) fluid replacement and aluminum hydroxide gel. Oxnard,
O'Bell, and Grupe (Ref. 13) reported that a 4-year-old child with
chronic renal failure became profoundly hyperphosphatemic and
hypocalcemic after receiving an entire adult sodium phosphates enema.
The child developed muscle twitching, acidosis, severe diarrhea, and
tachycardia, and was hospitalized, subsequently responding to IV
calcium gluconate, calcium chloride, and sodium bicarbonate.
Other authors have reported that children (4 months to 2 1/2 years
old) with gastrointestinal anomalies, such as Hirschsprung's disease
(congenital megacolon), and chronic renal failure were at high risk for
complications after the use of sodium phosphates enemas (Refs. 13
through 20). These children received varying amounts of adult or
pediatric sodium phosphates enemas for constipation and bowel cleansing
prior to surgery. Three of the children had cardiac arrest after the
use of hypertonic sodium phosphates enemas (Refs. 17, 19, and 20).
Martin et al. (Ref. 19) reported that an 11-month-old child died after
receiving four adult sodium phosphates enemas. Loughnan and Mullins
(Ref. 17) reported that a 9-month-old child suffered severe and
permanent brain damage after receiving a pediatric sodium phosphates
enema. Reedy and Zwiren (Ref. 20) reported that a 17-month-old child
received two pediatric sodium phosphates enemas as a ``bowel prep'' on
the day of surgery and was successfully resuscitated after experiencing
cardiac arrest during induction of anesthesia. The authors noted that
the child had received sodium phosphates enemas chronically but that a
possible electrolyte imbalance was not suspected, and the child was not
screened for any possible electrolyte problems prior to surgery.
[[Page 27841]]
Other authors (Refs. 21, 22, and 23) have reported acidosis,
hypocalcemia, and hyperphosphatemia that occurred in adults and
children after the use of sodium phosphates enema products. Davis et
al. (Ref. 21) state that these products can cause electrolyte
imbalances, which can cause severe reactions and could result in death,
when administered in the recommended doses to individuals with normal
renal function.
The agency is also aware of serious electrolyte imbalances
occurring in individuals who used more than one sodium phosphates enema
in a 24-hour period (Refs. 15, 16, 24, 25, and 26). Thus, an
electrolyte imbalance can result from an excess dose of either the oral
solution or the enema dosage form. Because of the serious side effects
that can occur from overdosage, the agency considers it important to
include information against exceeding the recommended dose of sodium
phosphates drug products in both the warnings and directions sections
of product labeling. The agency concludes that this information needs
to be required, not just voluntarily included at a manufacturer's
discretion.
III. References
The following references are on display in the Dockets Management
Branch (address above) and may be seen by interested persons between 9
a.m. and 4 p.m., Monday through Friday.
1. The United Stated Pharmacopeia 22/ The National Formulary 17,
The United States Pharmacopeial Convention Inc., Rockville, MD, pp.
1265-1267, 1989.
2. The United States Pharmacopeia 23/ The National Formulary 18,
The United States Pharmacopeial Convention Inc., Rockville, MD, pp.
1428-1430, 1994.
3. United States Pharmacopeia Dictionary of United States
Adopted Names and International Drug Names, The United States
Pharmacopeial Convention Inc., Rockville, MD, p. 658, 1997.
4. Clarkston, W. K. et al., ``A Single Blind Comparison of Serum
Electrolytes, Serum Phosphorus, Serum Calcium, and Ventricular
Arrhythmias in Outpatients Receiving Nulytely Versus Fleet Phospho-
Soda Preparation for Colonoscopy: Preliminary Results (unpublished
study),'' pp. 1-28, 1994, OTC vol. 090TFM4, Docket No. 78N-036L,
Dockets Management Branch.
5. Vanner, S. J. et al., ``A Randomized Prospective Trial
Comparing Oral Sodium Phosphate with Standard Polyethylene Glycol-
Based Lavage Solution (GoLytely) in the Preparation of Patients for
Colonoscopy,'' The American Journal of Gastroenterology, 85:422-427,
1990.
6. Warner, B. A., and J. A. DiPalma, ``Oral Sodium Phosphate
Catharsis: `First Do No Harm','' The American Journal of
Gastroenterology, 89:1118-1119, 1994.
7. Kolts, B. E. et al., ``A Comparison of the Effectiveness and
Patient Tolerance of Oral Sodium Phosphate, Castor Oil, and Standard
Electrolyte Lavage for Colonoscopy or Sigmoidoscopy Preparation,''
The American Journal of Gastroenterology, 88:1218-1223, 1993.
8. Kolts, B. E., ``Response to Drs. Warner and DiPalma,'' The
American Journal of Gastroenterology, 89:1119, 1994.
9. Cagir, B. et al., ``Hypocalcemia in Surgical Critical Care
Patients: Measurements of Ionized Calcium,'' Contemporary Surgery,
45:71-78, 1994.
10. Physicians' Desk Reference, 50th ed., Medical Economics Data
Production Co., Montvale, NJ, pp. 1002-1004, 1996.
11. Letter from W. E. Gilbertson, FDA, to P. Reichertz, Arent,
Fox, Kintner, Plotkin & Kahn, dated March 1, 1996, coded as LET109,
Docket No. 78N-036L, Dockets Management Branch.
12. Wason, S. et al., ``Severe Hyperphosphatemia, Hypocalcemia,
Acidosis, and Shock in a 5-Month Old Child Following the
Administration of an Adult Fleet Enema,'' Annals of Emergency
Medicine, 18:696-700, 1989.
13. Oxnard, S. C., J. O'Bell, and W.E. Grupe, ``Severe Tetany in
an Azotemic Child Related to a Sodium Phosphate Enema,'' Pediatrics,
53:105-106, 1974.
14. Chesney, R. W., and P. B. Haughton, ``Tetany Following
Phosphate Enemas in Chronic Renal Disease,'' American Journal of
Diseases of Children, 127:584-586, 1974.
15. Honig, P. J., and P. G. Holtzapple, ``Hypocalcemic Tetany
Following Hypertonic Phosphate Enemas,'' Clinical Pediatrics,
14:678-679, 1975.
16. Sotos, J. F. et al., ``Hypocalcemic Coma Following Two
Pediatric Phosphate Enemas,'' American Academy of Pediatrics,
60:305-307, 1977.
17. Loughnan, P., and G. C. Mullins, ``Brain Damage Following a
Hypertonic Phosphate Enema,'' American Journal of Diseases of
Children, 131:1032, 1977.
18. Forman, J., H. J. Baluarte, and A. B. Gruskin, ``Hypokalemia
After Hypertonic Phosphate Enemas,'' Journal of Pediatrics, 94:149-
151, 1979.
19. Martin, R. R. et al., ``Fatal Poisoning From Sodium
Phosphate Enema, Case Report and Experimental Study,'' Journal of
the American Medical Association, 257:2190-2192, 1987.
20. Reedy, J. C., and G. T. Zwiren, ``Enema-Induced Hypocalcemia
and Hyperphosphatemia Leading to Cardiac Arrest during Induction of
Anesthesia in an Outpatient Surgery Center,'' Anesthesiology,
59:578-579, 1983.
21. Davis, R. et al., ``Hypocalcemia, Hyperphosphatemia, and
Dehydration Following a Single Hypertonic Phosphate Enema,'' Journal
of Pediatrics, 90:484-485, 1977.
22. Swerdlow, D. B., S. Labow, and F. J. D'Anna, ``Tetany and
Enemas: Report of a Case,'' Diseases of the Colon and the Rectum,
17:786-787, 1973.
23. Biberstein, M., and B. A. Parker, Enema-Induced
Hyperphosphatemia, The American Journal of Medicine, 79:645-646,
1985.
24. Fonkalsrud, E., and J. Keen, ``Hypernatremic Dehydration
Hypertonic Enemas in Congenital Megacolon,'' The Journal of the
American Medical Association, 199:574-586, 1967.
25. Grosskopf, I. et al., ``Hyperphosphatemia and Hypocalcaemia
Induced by Hypertonic Phosphate Enema--An Experimental Study and
Review of the Literature,'' Human and Experimental Toxicology,
10:351-355, 1991.
26. Rohack, J. J., B. R. Mehta, and K. Subramanyam,
``Hyperphosphatemia and Hypocalcemic Coma Associated with Phosphate
Enema,'' South Medical Journal, 78:1241-1242, 1985.
IV. Summary of Significant Changes From the Proposed Rule
The agency is making the following changes based on comments
submitted in response to the proposal (59 FR 15139) and other relevant
information that has come to the agency's attention. The agency had
proposed to include the package size limitation and the labeling in the
final monograph for OTC laxative drug products (proposed 21 CFR part
334). However, that final monograph has not been completed to date.
Therefore, at this time the agency is including this information in
part 201 subpart G, Specific Labeling Requirements for Specific Drug
Products. New Sec. 201.307 will be titled Sodium phosphates; package
size limitation, warnings, and directions for over-the-counter sale.
When the laxative final monograph is complete, it will incorporate the
requirements in Sec. 201.307. A summary of the changes made by the
agency follows:
1. The package size limitation of 90 mL (3 oz) for sodium
phosphates oral solution proposed in Sec. 334.25 appears in
Sec. 201.307(b)(1) and is effective 30 days after date of publication
of this final rule in the Federal Register. The relabeling requirements
in Sec. 201.307 are effective 120 days after date of publication of
this final rule in the Federal Register. (See comment 2 in section II
of this document.)
2. The agency has revised the warning for oral and rectal dosage
forms of sodium phosphates proposed in Sec. 334.58(c)(2)(iv). The
agency is adding a new warning for oral sodium phosphates products,
which appears in Sec. 201.307(b)(2)(i) and states: ``Taking more than
the recommended dose in 24 hours can be harmful.'' (See comment 5 in
section II of this document.) The agency is adding a new warning for
rectal sodium phosphates products, which appears in
Sec. 201.307(b)(2)(ii) and states: ``Using more than one enema in 24
hours can be harmful.'' These warnings must appear in boldface type and
must be the first statement in product labeling under the heading
``Warnings.''
[[Page 27842]]
3. The agency is adding new directions in Sec. 201.307(b)(3)(i) for
oral and rectal sodium phosphates that state: ``Do not'' (``take'' or
``use'') ``more unless directed by a doctor. See Warnings.'' (See
comment 4 in section II of this document.) These directions must be in
boldface type and immediately precede the dosage information.
4. The agency is including specific directions in
Sec. 201.307(b)(3)(ii) that inform consumers not to take more than the
recommended daily dose in a 24-hour period. (See comment 3 in section
II of this document.)
V. The Agency's Final Conclusions on OTC Laxative Drug Products
Containing Sodium Phosphates
The agency has determined that there is sufficient evidence to show
that an overdose of sodium phosphates products can cause an electrolyte
imbalance. This imbalance can occur if an excess dose of either the
sodium phosphates oral solution or the sodium phosphates enema were
used. This electrolyte imbalance can cause severe reactions and result
in death. Accordingly, this final rule establishes a container size
limit for oral sodium phosphates products and new warning and direction
statements for OTC laxative drug product containing sodium phosphates.
To better protect consumers who use products containing these
ingredients, the agency concludes that the container size must be
limited to 90 mL (3 oz). In addition, labeling needs to alert consumers
not to exceed the recommended dose of an oral or rectal sodium
phosphates product in a 24-hour period. Therefore, the agency is
requiring the following warning for oral dosage forms of sodium
phosphates in Sec. 201.307(b)(2)(i): ``Taking more than the recommended
dose in 24 hours can be harmful.'' The agency is also requiring a
similar warning for rectal dosage forms of sodium phosphates in
Sec. 201.307(b)(2)(ii): ``Using more than one enema in 24 hours can be
harmful.'' Furthermore, the agency is requiring that the directions for
oral and rectal sodium phosphates products in Sec. 201.307(b)(3)(i)
state: ``Do not'' (``take'' or ``use'') ``more unless directed by a
doctor. See Warnings.'' These additional statements are intended to
refer consumers to the warnings when they read the directions for the
product. Because of the dire consequences that can occur from an
overdose of sodium phosphates, the warnings are required to appear in
boldface type as the first sentence under the heading ``Warnings.'' The
direction statements are required to appear in boldface type
immediately preceding the dosage information. In addition, the agency
is including specific directions that inform consumers not to take more
than the recommended daily dose in a 24-hour period in
Sec. 201.307(b)(3)(ii). (See comment 3 in section II of this document.)
VI. Analysis of Impacts
No comments were received in response to the agency's request for
specific comment on the economic impact of this rulemaking (59 FR 15139
at 15141). FDA has examined the impacts of the final rule under
Executive Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-
612). Executive Order 12866 directs agencies to assess all costs and
benefits of available regulatory alternatives and, when regulation is
necessary, to select regulatory approaches that maximize net benefits
(including potential economic, environmental, public health and safety,
and other advantages; distributive impacts; and equity). Under the
Regulatory Flexibility Act, if a rule has a significant economic impact
on a substantial number of small entities, an agency must analyze
regulatory options that minimize any significant impact of the rule on
small entities.
Title II of the Unfunded Mandates Reform Act (2 U.S.C. 1501 et
seq.) requires that agencies prepare a written statement and economic
analysis before proposing any rule that may result in an expenditure in
any one year by State, local, and tribal governments, in the aggregate,
or by the private sector, of $100 million (adjusted annually for
inflation). The proposed rule that has led to the development of this
final rule was published on March 31, 1994, before the Unfunded
Mandates Reform Act was enacted. The agency explains in this final rule
that the final rule will not result in an expenditure in any 1 year by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100 million.
The agency believes that this final rule is consistent with the
principles set out in the Executive Order and in these two statutes.
The purpose of this final rule is to limit the OTC container size of
one laxative drug product (sodium phosphates oral solution) to not more
than 90 mL and to add warning and direction statements to the labeling
of oral and rectal OTC sodium phosphates drug products. This container
size limitation and the warning and direction statements concern
product toxicity and are intended to help ensure the safe and effective
use of all OTC sodium phosphates drug products. Potential benefits
include reduced toxicity when consumers use these products.
The manufacturer of the only major trade product containing sodium
phosphates oral solution marketed in a container size larger that 90 mL
has already withdrawn that size product from the market. The agency is
not able to identify any other sodium phosphates oral solution marketed
by another manufacturer in a container exceeding 90 mL.
Regarding relabeling, the agency has been informed that relabeling
costs of the type required by this final rule generally average about
$2,000 to $3,000 per stock keeping unit (SKU) (individual products,
packages, and sizes). The agency is aware of 3 manufacturers that
together produce 4 SKU's of oral sodium phosphates drug products and
approximately 125 SKU's of rectal sodium phosphates drug products.
There may be a few additional small manufacturers or a few additional
products in the marketplace that are not identified in the sources FDA
reviewed. Assuming that there are about 130 affected OTC SKU's in the
marketplace, total one-time costs of relabeling would be $260,000 to
$390,000. The agency believes that actual cost could be lower for
several reasons. First, most of the label changes will be made by
private label manufacturers that tend to use simpler and less expensive
labeling. Second, the agency is allowing supplementary labeling (e.g.,
stick-on labeling) to be used for those products not undergoing a new
labeling printing within 120 days.
The final rule would not require any new reporting and
recordkeeping activities. Therefore, no additional professional skills
are needed. There are no other Federal rules that duplicate, overlap,
or conflict with the final rule.
The agency considered but rejected several container size and
labeling alternatives: (1) A container size limit of 45, 60, or 120 mL;
(2) voluntary relabeling; (3) publication of the labeling information
in the FDA Drug Bulletin or professional journals; and (4) an exemption
from coverage for small entities. The alternate container sizes were
not selected because 90 mL represents the upper limit of the two doses
per container and physicians often prescribe this amount for bowel
cleansing prior to surgery and diagnostic procedures of the colon. The
agency does not consider voluntary relabeling or an exemption from
coverage acceptable because they do not assure that consumers or health
professionals will have the most recent needed information for safe and
effective use of these sodium
[[Page 27843]]
phosphates drug products. The agency considers the third alternative
useful and may proceed with such publications. However, such
publications do not provide a permanent labeling requirement, which the
agency considers necessary for these products.
This final rule may have a significant economic impact on the
manufacturers of this product, all of which are considered small
entities, using the U.S. Small Business Administration designations for
this industry (750 employees). The agency believes that any other
unidentified manufacturer of these products may also be a small entity.
These manufacturers will need to change the information panel of each
affected sodium phosphates SKU. Among the steps the agency is taking to
minimize the impact on these small entities are: (1) To provide 120
days for implementation, as one comment requested, to enable entities
to use up some existing labeling stock, and (2) to provide for the use
of supplementary labeling (e.g., stick-on labeling) if necessary. The
agency believes that these actions should help reduce the relabeling
cost for small entities.
The agency considered a longer implementation period. The agency
proposed a 30-day effective date, considered extending this to 60 days,
and in response to public comment has extended the effective date to
120 days to reduce the economic burden on small entities. The agency
considered but rejected a longer effective date because it would not
assure that consumers have the most recent needed information for safe
and effective use of OTC sodium phosphates drug products at the
earliest possible time. The agency concludes that the overriding safety
considerations warrant a 120-day implementation period.
The analysis shows that this final rule is not economically
significant under Executive Order 12866 and that the agency has
undertaken important steps to reduce the burden to small entities.
Nevertheless, some entities, especially those private label
manufacturers that provide labeling for a number of the affected
products, may incur significant impacts. Thus, this economic analysis,
together with other relevant sections of this document, serves as the
agency's final regulatory flexibility analysis, as required under the
Regulatory Flexibility Act. Finally, this analysis shows that the
Unfunded Mandates Act does not apply to the final rule because it would
not result in an expenditure in any one year by State, local, and
tribal governments, in the aggregate, or by the private sector, of $100
million.
VII. Paperwork Reduction Act of 1995
FDA concludes that the labeling requirements in this document are
not subject to review by the Office of Management and Budget because
they do not constitute a ``collection of information'' under the
Paperwork Reduction Act of 1995 (44 U.S.C. 3501 et seq.). Rather, the
labeling statements are a ``public disclosure of information orginally
supplied by the Federal government to the recipient for the purpose of
disclosure to the public'' (5 CFR 1320.3(c)(2)).
VIII. Environmental Impact
The agency has determined under 21 CFR 25.31(c) 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.
List of Subjects in 21 CFR Part 201
Drugs, Labeling, Reporting and recordkeeping requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act, and
under authority delegated to the Commissioner of Food and Drugs, 21 CFR
part 201 is amended as follows:
PART 201--LABELING
1. The authority citation for 21 CFR part 201 continues to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357,
358, 360, 360b, 360gg-360ss, 371, 374, 379e; 42 U.S.C. 216, 241,
262, 264.
2. Section 201.307 is added to subpart G to read as follows:
Sec. 201.307 Sodium phosphates; package size limitation, warnings, and
directions for over-the-counter sale.
(a) Reports in the medical literature and data accumulated by the
Food and Drug Administration indicate that multiple container sizes of
sodium phosphates oral solution available in the marketplace have
caused consumer confusion and appear to have been involved in several
consumer deaths. Sodium phosphates oral solution has been marketed in
45-milliliter (mL), 90-mL, and 240-mL container sizes. The 45-mL and
90-mL container sizes of sodium phosphates oral solution are often
recommended and prescribed by physicians for bowel cleansing prior to
surgery and diagnostic procedures of the colon. Sodium phosphates oral
solution (adult dose 20 mL to 45 mL) is also used as an over-the-
counter (OTC) laxative for the relief of occasional constipation.
Accidental overdosing and deaths have occurred because the 240-mL
container was mistakenly used instead of the 45-mL or 90-mL container.
The Food and Drug Administration is limiting the amount of sodium
phosphates oral solution to not more than 90 mL (3 ounces (oz)) per OTC
container because of the serious health risks associated with the
ingestion of larger than intended doses of this product. Further,
because an overdose of either oral or rectal enema sodium phosphates
can cause an electrolyte imbalance, additional warning and direction
statements are required for the safe use of any OTC laxative drug
product containing sodium phosphates.
(b) Any OTC drug product for laxative or bowel cleansing use
containing sodium phosphates as an active ingredient when marketed as
described in paragraph (a) of this section is misbranded within the
meaning of section 502 of the Federal Food, Drug, and Cosmetic Act
unless packaged and labeled as follows:
(1) Package size limitation for sodium phosphates oral solution:
Container shall not contain more than 90 mL (3 oz).
(2) Warnings. The following sentences shall appear in boldface type
as the first statement under the heading ``Warnings.''
(i) Oral dosage forms. ``Taking more than the recommended dose in
24 hours can be harmful.''
(ii) Rectal enema dosage forms. ``Using more than one enema in 24
hours can be harmful.''
(3) Directions--(i) The labeling of all orally or rectally
administered OTC drug products containing sodium phosphates shall
contain the following directions in boldface type immediately preceding
the dosage information: ``Do not'' (``take'' or ``use'') ``more unless
directed by a doctor. See Warnings.''
(ii) For products containing dibasic sodium phosphate/monobasic
sodium phosphate identified in Sec. 334.16(d) marketed as a solution.
Adults and children 12 years of age and over: Oral dosage is dibasic
sodium phosphate 3.42 to 7.56 grams (g) and monobasic sodium phosphate
9.1 to 20.2 g (20 to 45 mL dibasic sodium phosphate/monobasic sodium
phosphate oral solution) as a single daily dose. ``Do not take more
than 45 mL (9 teaspoonfuls or 3 tablespoonfuls) in a 24-hour period.''
Children 10 and 11 years of age: Oral dosage is dibasic sodium
phosphate 1.71 to 3.78 g and monobasic sodium phosphate 4.5 to 10.1 g
(10 to 20 mL dibasic sodium phosphate/monobasic sodium phosphate oral
solution) as a single daily dose. ``Do not take more than 20 mL (4
teaspoonfuls) in a 24-
[[Page 27844]]
hour period.'' Children 5 to 9 years of age: Oral dosage is dibasic
sodium phosphate 0.86 to 1.89 g and monobasic sodium phosphate 2.2 to
5.05 g (5 to 10 mL dibasic sodium phosphate/monobasic sodium phosphate
oral solution) as a single daily dose. ``Do not take more than 10 mL (2
teaspoonfuls) in a 24-hour period.'' Children under 5 years of age: ask
a doctor.
(c) After June 22, 1998, for package size limitation and September
18, 1998, for labeling in accord with paragraph (b) of this section,
any such OTC drug product initially introduced or initially delivered
for introduction into interstate commerce, or any such drug product
that is repackaged or relabeled after these dates regardless of the
date the product was manufactured, initially introduced, or initially
delivered for introduction into interstate commerce, that is not in
compliance with this section is subject to regulatory action.
Dated: April 28, 1998.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 98-12053 Filed 5-20-98; 8:45 am]
BILLING CODE 4160-01-F