[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