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

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.

-----------------------------------------------------------------------

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.

---------------------------------------------------------------------------

\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.

---------------------------------------------------------------------------

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