27836 Federal Register / Vol. 63, No. 98 /Thursday, May 21, 1998 /Rules and Regulations

concludes that the proposed use of the

additive is safe, that the additive will

achieve its intended technical effect,

and therefore, that the regulations in

§ 178.2010 should be amended as set

forth below.

In accordance with § 171.1(h) (21 CFR

171.1(h)), the petition and the

documents that FDA considered and

relied upon in reaching its decision to

approve the petition are available for

inspection at the Center for Food Safety

and Applied Nutrition by appointment

with the information contact person

listed above. As provided in § 171.1(h),

the agency will delete from the

documents any materials that are not

available for public disclosure before

making the documents available for

inspection.

The agency has carefully considered

the potential environmental effects of

this action. FDA has concluded that the

action will not have a significant impact

on the human environment, and that an

environmental impact statement is not

required. The agency’s finding of no

significant impact and the evidence

supporting that finding, contained in an

environmental assessment, may be seen

in the Dockets Management Branch

(address above) between 9 a.m. and 4

p.m., Monday through Friday.

Any person who will be adversely

affected by this regulation may at any

time on or before June 22, 1998, file

with the Dockets Management Branch

(address above) written objections

thereto. Each objection shall be

separately numbered, and each

numbered objection shall specify with

particularity the provisions of the

regulation to which objection is made

and the grounds for the objection. Each

numbered objection on which a hearing

is requested shall specifically so state.

Failure to request a hearing for any

particular objection shall constitute a

waiver of the right to a hearing on that

objection. Each numbered objection for

which a hearing is requested shall

include a detailed description and

analysis of the specific factual

information intended to be presented in

support of the objection in the event

that a hearing is held. Failure to include

such a description and analysis for any

particular objection shall constitute a

waiver of the right to a hearing on the

objection. Three copies of all documents

shall be submitted and shall be

identified with the docket number

found in brackets in the heading of this

document. Any objections received in

response to the regulation may be seen

in the Dockets Management Branch

between 9 a.m. and 4 p.m., Monday

through Friday.

List of Subjects in 21 CFR Part 178

Food additives, Food packaging.

Therefore, under the Federal Food,

Drug, and Cosmetic Act and under

authority delegated to the Commissioner

of Food and Drugs and redelegated to

the Director, Center for Food Safety and

Applied Nutrition, 21 CFR part 178 is

amended as follows:

PART 178—INDIRECT FOOD

ADDITIVES: ADJUVANTS,

PRODUCTION AIDS, AND SANITIZERS

1. The authority citation for 21 CFR

part 178 continues to read as follows:

Authority: 21 U.S.C. 321, 342, 348, 379e.

2. Section 178.2010 is amended in the

table in paragraph (b) by alphabetically

adding a new entry under the headings

‘‘Substances’’ and ‘‘Limitations’’ to read

as follows:

§ 178.2010 Antioxidants and/or stabilizers

for polymers.

* * * * *

(b) * * *

Substances Limitations

* * * * * * *

1, 11-(3, 6, 9-Trioxaundecyl) bis-3-(dodecylthio) propionate (CAS Reg.

No. 64253–30–1).

For use only as provided in § 175.300(b)(3)(xxxi) of this chapter at 4.0

parts per 100 parts rubber.

* * * * * * *

Dated: May 11, 1998.

L. Robert Lake,

Director, Office of Policy, Planning and

Strategic Initiatives, Center for Food Safety

and Applied Nutrition.

[FR Doc. 98–13469 Filed 5–20–98; 8:45 am]

BILLING CODE 4160–01–F

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 Overthe-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-thecounter (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
Federal Register / Vol. 63, No. 98 /Thursday, May 21, 1998 /Rules and Regulations 27837

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.

2Sodium 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.

§ 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 § 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 § 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 xray or endoscopic examination. (See

proposed § 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.

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
27838 Federal Register / Vol. 63, No. 98 /Thursday, May 21, 1998 /Rules and Regulations

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., stickon 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 § 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 § 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

§ 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

§ 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
Federal Register / Vol. 63, No. 98 /Thursday, May 21, 1998 /Rules and Regulations 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
27840 Federal Register / Vol. 63, No. 98 /Thursday, May 21, 1998 /Rules and Regulations

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 § 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 § 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 § 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.
Federal Register / Vol. 63, No. 98 /Thursday, May 21, 1998 /Rules and Regulations 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, ‘‘EnemaInduced 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 § 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

§ 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 § 334.25 appears in

§ 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 § 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

§ 334.58(c)(2)(iv). The agency is adding

a new warning for oral sodium

phosphates products, which appears in

§ 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 § 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.’’
27842 Federal Register / Vol. 63, No. 98 /Thursday, May 21, 1998 /Rules and Regulations

3. The agency is adding new

directions in § 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 § 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

§ 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

§ 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

§ 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 § 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
Federal Register / Vol. 63, No. 98 /Thursday, May 21, 1998 /Rules and Regulations 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:

§ 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 § 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-
27844 Federal Register / Vol. 63, No. 98 /Thursday, May 21, 1998 /Rules and Regulations

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

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Part 510

Animal Drugs, Feeds, and Related

Products; Change of Sponsor Name

AGENCY: Food and Drug Administration,

HHS.

ACTION: Final rule.

SUMMARY: The Food and Drug

Administration (FDA) is amending the

animal drug regulations to reflect the

change of sponsor name from Protiva, a

unit of Monsanto, to Monsanto Co.

EFFECTIVE DATE: May 21, 1998.

FOR FURTHER INFORMATION CONTACT:

Thomas J. McKay, Center for Veterinary

Medicine (HFV–102), Food and Drug

Administration, 7500 Standish Pl.,

Rockville, MD 20855, 301–827–0213.

SUPPLEMENTARY INFORMATION: Protiva, a

unit of Monsanto has informed FDA of

a change of sponsor name to Monsanto

Co. Accordingly, FDA is amending 21

CFR 510.600(c)(1) and (c)(2) to reflect

the change of sponsor name.

List of Subjects in 21 CFR Part 510

Administrative practice and

procedure, Animal 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 and redelegated to

the Center for Veterinary Medicine, 21

CFR part 510 is amended as follows:

PART 510—NEW ANIMAL DRUGS

1. The authority citation for 21 CFR

part 510 continues to read as follows:

Authority: 21 U.S.C. 321, 331, 351, 352,

353, 360b, 371, 379e.

§ 510.600 [Amended]

2. Section 510.600 Names, addresses,

and drug labeler codes of sponsors of

approved applications is amended in

the table in paragraph (c)(1) by

removing the entry for ‘‘Protiva, A Unit

of Monsanto Co.’’ and by alphabetically

adding a new entry for ‘‘Monsanto Co.,

800 North Lindbergh Blvd., St. Louis,

MO 63167’’ and in the table in

paragraph (c)(2) in the entry for

‘‘059945’’ by removing the sponsor

name ‘‘Protiva, A Division of Monsanto

Co.’’ and adding in its place ‘‘Monsanto

Co.’’

Dated: May 8, 1998.

Andrew J. Beaulieu,

Acting Director, Office of New Animal Drug

Evaluation, Center for Veterinary Medicine.

[FR Doc. 98–13162 Filed 5–20–98; 8:45 am]

BILLING CODE 4160–01–F

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 510 and 558

Animal Drugs, Feeds, and Related

Products; Change of Sponsor

AGENCY: Food and Drug Administration,

HHS.

ACTION: Final rule.

SUMMARY: The Food and Drug

Administration (FDA) is amending the

animal drug regulations to reflect a

change of sponsor for 96 new animal

drug applications (NADA’s) and 4

abbreviated animal drug applications

(ANADA’s) from Hoffmann-La Roche,

Inc., to Roche Vitamins, Inc.

EFFECTIVE DATE: May 21, 1998.

FOR FURTHER INFORMATION CONTACT:

Thomas J. McKay, Center for Veterinary

Medicine (HFV–102), Food and Drug

Administration, 7500 Standish Pl.,

Rockville, MD 20855, 301–827–0213.

SUPPLEMENTARY INFORMATION: HoffmannLa Roche, Inc., Nutley, NJ 07110, has

informed FDA that it has transferred the

ownership of and all rights and interests

in approved NADA’s and ANADA’s to

Roche Vitamins, Inc., 45 Waterview

Blvd., Parsippany, NJ 07054–1298.

Accordingly, the agency is amending

the regulations in 21 CFR parts 510 and

558 to reflect the change of sponsor. The

agency is also amending the regulations

in § 510.600(c)(1) and (c)(2) by removing

Hoffmann-La Roche, Inc., because the

sponsor no longer sponsors any

approved new animal drugs, and by

alphabetically adding an entry for Roche

Vitamins, Inc.

List of Subjects

21 CFR Part 510

Administrative practice and

procedure, Animal drugs, Labeling,

Reporting and recordkeeping

requirements.

21 CFR Part 558

Animal drugs, Animal feeds.

Therefore, under the Federal Food,

Drug, and Cosmetic Act and under

authority delegated to the Commissioner

of Food and Drugs and redelegated to

the Center for Veterinary Medicine, 21

CFR parts 510 and 558 are amended as

follows:

PART 510—NEW ANIMAL DRUGS

1. The authority citation for 21 CFR

part 510 continues to read as follows:

Authority: 21 U.S.C. 321, 331, 351, 352,

353, 360b, 371, 379e.

§ 510.600 Names, addresses, and drug

labeler codes of sponsors of approved

applications.

2. Section 510.600 is amended in the

table in paragraph (c)(1) by removing

the entry for ‘‘Hoffmann-La Roche,

Inc.,’’ and by alphabetically adding an

entry for ‘‘Roche Vitamins, Inc.,’’ and in

the table in paragraph (c)(2) by

removing the entry for ‘‘000004’’ and by

numerically adding an entry for

‘‘063238’’ to read as follows:

§ 510.600 Names, addresses, and drug

labeler codes of sponsors of approved

applications.

* * * * *

(c) * * *

(1) * * *