Laxative Drug Products for Over-the-Counter Human Use; Proposed Amendment to the Tentative Final Monograph

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 334

[Docket No. 78N-036L]

RIN 0910-AA01

Laxative Drug Products for Over-the-Counter Human Use; Proposed

Amendment to the Tentative Final Monograph

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice of proposed rulemaking.

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[[Page 27887]]

SUMMARY: The Food and Drug Administration (FDA) is amending the

tentative final monograph for over-the-counter (OTC) laxative drug

products to include additional general and professional labeling for

oral and rectal dibasic sodium phosphate/monobasic sodium phosphate

(sodium phosphates) drug products. FDA is proposing new warnings and

directions for these products and a new time to effect statement for

rectal products based on new data submitted after publication of the

tentative final monograph for OTC laxative drug products. This proposal

is part of the ongoing review of OTC drug products conducted by FDA.

Elsewhere in this issue of the Federal Register the agency is

finalizing the package size limitation and warning prior to the

completion of the final monograph for OTC laxative drug products.

DATES: Submit written comments or objections by August 19, 1998.

ADDRESSES: Submit written comments to the Dockets Management Branch

(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23,

Rockville, MD 20857.

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 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 biphosphate \1\ and sodium phosphate \2\ (40 FR

12902 at 12940).

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\1\ The Panel designated this ingredient ``sodium biphosphate.''

However, monobasic sodium phosphate is currently the official name

for this ingredient in the USP Dictionary of USAN and International

Drug Names, 1997.

\2\ The Panel designated this ingredient ``sodium phosphate.''

However, dibasic sodium phosphate is currently the official name for

this ingredient in the USP Dictionary of USAN and International Drug

Names, 1997.

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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 \3\. (See proposed

Sec. 334.58(d)(5)(i), 50 FR 2124 at 2152 and 2155.) In addition to its

use as an OTC laxative for the relief of occasional constipation,

sodium phosphates oral solution 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 \4\, respectively, are the current United States

Pharmacopeia (USP) names for the oral and rectal dosage forms of the

combination of sodium phosphates ingredients.

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\3\ 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.

\4\ Sodium phosphates enema is the official name for a solution

of dibasic sodium phosphate and monobasic sodium phosphate in the

U.S. Pharmacopeia 23/National Formulary 18, 1995.

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In the Federal Register of March 31, 1994 (59 FR 15139), the agency

proposed to amend the tentative final monograph for OTC laxative drug

products to limit the OTC container size for sodium phosphates oral

solution to not greater than 90 milliliters (mL). 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 volume 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 (59 FR 15139 at 15140).

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 a

warning (informing consumers not to exceed the recommended dosage

unless directed by a doctor) in the monograph for OTC laxative drug

products. However, that monograph has not been finalized to date.

Because of the potential serious safety risk involved, elsewhere in

this issue of the Federal Register the agency is finalizing the package

size limitation and warning prior to the completion of the final

monograph for OTC laxative drug products. The agency is including this

information in part 201 (21 CFR part 201) at this time and will

incorporate it into the final monograph for OTC laxative drug products

at a later date.

Based on new data submitted since the January 15, 1985, and the

March 31, 1994, proposals were published, the agency is proposing in

this document additional general and professional labeling for oral and

rectal sodium phosphates products for OTC laxative use. 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. When the

agency finalizes that proposal, the agency will also amend the final

version of the rule proposed herein, as needed, to conform to the final

labeling rule. Copies of previous rulemakings discussed above and

information that has come to the agency's attention since publication

of the proposals are on public display in the Dockets Management Branch

(address above).

II. The Agency's Labeling Proposals for Sodium Phosphates

A. Introduction

One comment informed the agency of modifications made in the

labeling of its rectal enema sodium phosphates product. The comment had

expanded the professional labeling to include additional warning

statements regarding use in patients with a colostomy, congenital

megacolon, imperforate anus, impaired renal function, heart disease,

congestive heart failure, preexisting electrolyte disturbances (such as

dehydration or those secondary to the use of diuretics), or in patients

using calcium channel blockers, diuretics, or other medications that

may affect electrolyte levels, as hypocalcemia, hyperphosphatemia,

hypernatremia, and acidosis may occur. The comment cited several

references (Refs. 1, 2, and 3) to support its warning statements. The

professional labeling also included information on the treatment of

electrolyte imbalances. The comment stated that the labeling no longer

recommends the use of this enema product in children under 2 years of

age. The comment mentioned that a summarized version of the

professional

[[Page 27888]]

labeling will appear on the product's retail carton.

The agency agrees with the comment that the professional labeling

for these sodium phosphates products should be expanded to include more

information for health professionals to ensure safe use. As a result of

the comment's additional warnings, the agency has reevaluated all of

the labeling for sodium phosphates products (oral and rectal). The

agency notes that the comment included calcium channel blockers in its

professional warning. However, the agency is not aware of any specific

data to show that sodium phosphates products should not be used in

patients taking calcium channel blockers. Therefore, calcium channel

blockers will not be included in the professional warning for sodium

phosphates products at this time.

B. Professional Labeling

In Sec. 334.80(b)(2) of the tentative final monograph for OTC

laxative drug products (50 FR 2124 at 2157), the agency proposed the

following warnings in the professional labeling for products containing

sodium phosphates: ``Do not use in patients with megacolon, as

hypernatremic dehydration may occur. Use with caution in patients with

impaired renal function.'' The comment's labeling and information in

the literature provide a basis to expand this warning. Individuals with

impaired renal function (Refs. 4 through 8, including the elderly (Ref.

5)), heart disease (Refs. 8, 9, and 10), acute myocardial infarction

(Refs. 11 and 12), unstable angina (Ref. 12), dehydration (Refs. 1 and

9), or who are on diuretics (Ref. 10) are at risk for an electrolyte

imbalance to occur with use of oral and rectal sodium phosphates

products. Sodium phosphates can cause alterations in serum levels of

sodium, potassium, phosphate, chloride, and calcium and, in some

people, such changes can be life threatening. The reduction of calcium

levels reflects changes in ionized calcium (Ref. 13). Hypocalcemia with

subsequent low levels of ionized calcium may result in neuromuscular

irritability, heart block, and cardiovascular failure (Ref. 13).

Therefore, the agency has determined that the warnings in the

professional labeling for oral and rectal sodium phosphates products in

proposed Sec. 334.80(b)(2) (redesignated as Sec. 334.80(b)(2)(i) in

this proposal) should be expanded. The agency has made an effort to

present the warning information in a new format using specific headings

to make it clearer and more readable as follows:

``Do not use'' (these three words in bold print) ``in patients

with congestive heart failure.''

``Use with caution'' (these three words in bold print) ``in

patients with impaired renal function, heart disease, acute

myocardial infarction, unstable angina, preexisting electrolyte

disturbances (such as dehydration or those secondary to the use of

diuretics), the elderly, or people taking drugs that may affect

electrolyte levels.''

The agency is also including the following information regarding

prevention and treatment of an electrolyte imbalance.

``Monitor electrolytes.'' (these two words in bold print) ``Give

sufficient fluid replacement with all oral and rectal sodium

phosphates products to prevent dehydration.'' ``What can occur:''

(these three words in bold print) ``Hypocalcemia, hyperphosphatemia,

hypernatremia, hypokalemia, and acidosis. These conditions are more

likely to occur when more than one dose of sodium phosphates is

given in a 24-hour period.''

``What you should do:'' (these four words in bold print)

``Advise people to follow recommended dose. Treatment of electrolyte

imbalance may require immediate medical intervention with

appropriate electrolyte and fluid replacement. (Some examples of

references for treatment of this condition are Fonkalsrud, E., and

J. Keen, Hypernatremic Dehydration Hypertonic Enemas in Congenital

Megacolon, The Journal of the American Medical Association,

199:584586, 1967, and Edmondson, S., and T. D. Almquist, Iatrogenic

Hypocalcemic Tetany, Annals of Emergency Medicine, 19:938-940,

1990.)''

The agency is including additional warnings for rectal sodium

phosphates products because of reports of its misuse in certain

individuals by health professionals. Fatal or life-threatening

consequences have resulted from excess dosages of sodium phosphates

enemas in adults (Refs. 4, 6, and 14) and in young children (Refs. 10,

15, and 16). The agency notes that many of these adverse effects

occurred when sodium phosphates enemas were used in children under 2

years of age. Sodium phosphates enemas have also been misused in

individuals with colon abnormalities (Refs. 1, 4, 10, 17, and 18) and

rectal abnormalities (Refs. 5, 19, and 20). Individuals with a

functional abnormality of the colon, e.g., a colostomy (Refs. 10, 21,

and 22), imperforate anus (Refs. 4 and 21), atonic colon (Ref. 4), or

congenital megacolon (Refs. 1, 4, 10, and 21) are at risk for

hyperosmotic dehydration and hyperphosphatemia with the use of sodium

phosphates enemas. Such individuals have a tendency to retain the enema

for a prolonged period of time, and considerable absorption of the

phosphate ion occurs. Several cases of rectal gangrene have occurred

after an enema nozzle injury in individuals with hemorrhoids (Refs. 19,

20, and 23). The authors believed that the rectal injury was compounded

due to the necrotizing effect of the sodium phosphates on the rectal

tissue. Other reports (Refs. 19, 20, and 23 through 26) indicate that

following an enema tip injury to the rectum, the presence of sodium

phosphates causes a pronounced inflammatory response and tissue damage

which, if untreated, can produce serious consequences. Based on the

above, the agency is proposing to add the following warnings in the

professional labeling in proposed Sec. 334.80(b)(2)(ii) for sodium

phosphates enemas to inform health professionals to carefully monitor

use in certain individuals or not to use at all. This information is

also presented in the new format using specific headings:

``Do not use'' (these three words in bold print) ``sodium

phosphates enema in children under 2 years of age or in patients

with congenital megacolon or imperforate anus because of the risk of

hyperosmotic dehydration and hyperphosphatemia.''

``Stop using'' (these two words in bold print) ``if there is

resistance to the enema tip. Forcing the tip into the rectum can

result in a serious injury that requires immediate medical

attention.''

``Use sodium phosphates enema with extreme caution'' (these

seven words in bold print) ``in patients with a colostomy or atonic

colon (because of the risk of hyperosmotic dehydration and

hyperphosphatemia) or with a rectal abnormality, such as hemorrhoids

(because sodium phosphates can cause serious damage to the rectal

mucosa if an enema tip injury occurs). Using more than one sodium

phosphates enema in a 24-hour period can cause serious electrolyte

problems.''

The ``Do not use'' warning for sodium phosphates enemas in

Sec. 334.80(b)(2)(ii)(A) may be combined with the ``Do not use''

warning for all sodium phosphates products in Sec. 334.80(b)(2)(i)(A).

The warning proposed for sodium phosphates products in

Sec. 334.80(b)(2) of the tentative final monograph, which stated ``Do

not use in patients with megacolon, as hypernatremic dehydration may

occur. Use with caution in patients with impaired renal function,'' is

superseded by the warnings in this amendment.

The agency notes that the comment stated that a summarized version

of the professional labeling will appear on the product's retail

package. Professional labeling is labeling provided to health

professionals but not to the general public. Therefore, a summarized

version of this professional labeling should not appear on the retail

package. As discussed in section II.C of this document, the agency has

developed labeling for sodium phosphates products that it believes

adequately

[[Page 27889]]

informs consumers of the proper use of these products.

C. OTC Labeling

In Sec. 334.58(c)(2)(i) of the tentative final monograph (50 FR

2124 at 2155), the agency proposed the following warning for products

containing sodium phosphates: ``Do not use this product if you have

kidney disease, unless directed by a doctor.'' The agency is proposing

to expand the warning for oral and rectal products that contain sodium

phosphates because consumers who have kidney disease (Refs. 4 through

7), heart problems (Refs. 8 through 12), or are dehydrated (Refs. 1 and

9) should not use sodium phosphates products, unless directed by a

doctor.

The agency has also determined that a new warning is needed to

restrict the number of days that all oral and rectal sodium phosphates

products can be used, unless directed by a doctor. The Panel in its

report (40 FR 12902 at 12941) and the agency in the tentative final

monograph (50 FR 2124 at 2153) recommended that the use of sodium

phosphates be restricted to 1 week (7 days). However, the agency has

reviewed new data indicating that sodium phosphates can cause

electrolyte imbalances within 24 hours after the initial dose is taken

(Refs. 4, 11, and 12) (also see the final rule for oral and rectal OTC

sodium phosphates drug products published elsewhere in this issue of

the Federal Register). These blood level changes have occurred in

individuals with no underlying renal failure or active heart disease

(Refs. 11, 12, and 27). The agency is concerned that daily use of

sodium phosphates products for 7 days may cause significant changes in

the sodium, potassium, phosphate, chloride, and/or calcium blood

levels. In the interest of consumer safety and to help reduce the risk

of adverse effects that can occur from sequential doses of sodium

phosphates, the agency believes that use of sodium phosphates should be

limited to 3 days instead of 7 days. The revised warning for oral and

rectal sodium phosphates, which appears in proposed

Sec. 334.58(c)(2)(i), states: ``Do not use if'' (these four words in

bold print) ``you have kidney disease, heart problems, or are

dehydrated, or for more than 3 days, without asking a doctor.''

In Sec. 334.58(c)(2)(ii) of the tentative final monograph (50 FR

2124 at 2155), the agency proposed the following warning for oral

dosage forms of sodium phosphates identified in Sec. 334.16(d), (e), or

(f): ``Do not give to children under 5 years of age unless directed by

a doctor.'' However, the agency is proposing to revise the directions

for oral sodium phosphates products in new Sec. 201.307(b)(3)(ii) (21

CFR 201.307(b)(3)(ii)) (designated as Sec. 334.58(d)(5)(i) in this

proposal) and in proposed Sec. 334.58(d)(6) and (d)(7) to be consistent

with other oral OTC laxative drug products. (See section II.D of this

document.) Therefore, for consistency, the proposed warning in

Sec. 334.58(c)(2)(ii) for oral sodium phosphates is revised to state:

``Do not give to children under 6 years of age, without asking a

doctor.''

In Sec. 334.58(c)(2)(iii) of the tentative final monograph (50 FR

2124 at 2155), the agency proposed the following warning for sodium

phosphates enemas: ``Do not give to children under 2 years of age

unless directed by a doctor.'' The agency also proposed the following

direction for sodium phosphates enemas in Sec. 334.58(d)(5)(ii) (50 FR

2124 at 2155): ``* * * Children under 2 years of age: consult a

doctor.'' However, because of adverse effects that have occurred when

sodium phosphates enemas were used in children under 2 years of age,

the agency is revising the warning and direction statements. Therefore,

in Sec. 334.58(c)(2)(iii) of this proposal, the revised warning for

sodium phosphates rectal products states: ``Do not use in children

under 2 years of age.'' The corresponding direction, which appears in

Sec. 334.58(d)(5)(ii)(A) in this proposal, is revised to state: ``* * *

Do not use in children under 2 years of age.'' The agency believes it

is necessary to have this information in both the warning and direction

sections of the labeling because of the adverse effects that can occur

when sodium phosphates enemas are used in children under 2 years of

age.

D. Directions

Effectiveness is not increased when a sodium phosphates enema is

retained more than 5 minutes (Refs. 28, 29, and 30). Data indicate that

a sodium phosphates enema is usually expelled from the rectum within 20

minutes (Refs. 28, 29, and 30) and that increased blood levels of

phosphorus and sodium and decreased levels of calcium can occur within

several hours (Refs. 13, 17, and 30) if the enema is retained.

Therefore, the agency is proposing a new direction for sodium

phosphates rectal products in Sec. 334.58(d)(5)(ii)(B) in this

proposal, which states: ``If no urge is felt after 5 minutes of using,

try to empty bowel. Call a doctor promptly if no liquid comes out of

the rectum after 30 minutes because dehydration could occur.''

The agency is proposing a new direction in Sec. 334.58(d)(5)(ii)(C)

for sodium phosphates rectal products. A sodium phosphates enema can

cause serious damage to the rectal mucosa if the enema tip causes a

rectal injury (Refs. 19, 20, and 23). If the enema tip perforates the

rectum, antibiotic treatment or a temporary colostomy may be needed to

prevent sepsis (Refs. 23 through 26, and 31). All rectal bleeding

resulting from an enema tip injury should be medically evaluated

because rectal perforations can be painless (Refs. 20, 25, and 31).

Therefore, the new direction states: ``Stop using if tip is hard to

insert. Forcing the tip into the rectum can cause injury (especially if

you have hemorrhoids). If enema tip causes rectal bleeding or pain, get

immediate medical care.''

The agency is aware that labeling that was submitted to the Panel

(Ref. 32) and currently marketed labeling (Ref. 33) for oral sodium

phosphates products contain dosages for children 5 to 9 years of age,

and for children 10 and 11 years of age. The Panel in its report (40 FR

12902 at 12940) and the agency in the tentative final monograph (50 FR

2124 at 2155) recommended dosages of oral sodium phosphates products

for these age groups. Elsewhere, in this issue of the Federal Register,

the agency included the above age ranges in the directions in new

Sec. 201.307(b)(3)(ii). 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, the agency is proposing to revise the directions for

oral sodium phosphates products in new Sec. 201.307(b)(3)(ii)

(designated as Sec. 334.58(d)(5)(i) in this proposal), and in proposed

Sec. 334.58(d)(6) and (d)(7) to be consistent with other oral OTC

laxative drug products. The proposed directions in Sec. 334.58(d)(5)(i)

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 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.

The proposed directions in Sec. 334.58(d)(6) for products containing

dibasic sodium phosphate identified in Sec. 334.16(e) state: ``* * *

Children 6 to 9 years of age: Oral dosage is 0.86 to 1.89 g in a single

daily dose. Children under 6 years of age: ask a doctor.'' The

[[Page 27890]]

proposed directions in Sec. 334.58(d)(7) for products containing

monobasic sodium phosphate identified in Sec. 334.16(f) state: ``* * *

Children 6 to 9 years of age: Oral dosage is 1.12 to 5.05 g in a single

daily dose. Children under 6 years of age: ask a doctor.''

E. Time to Effect

The agency is proposing to revise the time to effect statement in

proposed Sec. 334.58(b)(2) for sodium phosphates rectal products from 2

to 15 minutes to 1 to 5 minutes. In three studies (Refs. 28, 29, and

30), 98 subjects (280 observations) were evaluated to determine the

time to effect following use of sodium phosphates enema. In 98 percent

of the observations (33 subjects accounted for 261/280 observations),

the reported time to effect was within 10 minutes. In 83 percent of the

observations, the time to effect was between 1 and 5 minutes. The

average time to effect was 4 to 5 minutes and the mode was 3 to 5

minutes. The data do not indicate that sodium phosphates is more

effective if the solution is retained more than 5 minutes (Refs. 28,

29, and 30). Therefore, the agency is proposing to revise

Sec. 334.58(b)(2) to state: ``This product generally produces bowel

movement in 1 to 5 minutes.''

The agency invites specific comments on these proposed labeling

statements. The agency will discuss its decision on these labeling

proposals in a future issue of the Federal Register. Until the agency

makes a final determination on these labeling statements, the agency

encourages all manufacturers of sodium phosphates products voluntarily

to label their products to include the proposed labeling statements.

Because FDA is encouraging that the proposed labeling statements be

used on a voluntary basis at this time, the agency will give

manufacturers ample time after publication of a final rule to use up

any labeling implemented in conformance with this document.

III. References

The following references have been placed 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. Fonkalsrud, E., and J. Keen, ``Hypernatremic Dehydration

Hypertonic Enemas in Congenital Megacolon,'' The Journal of the

American Medical Association, 199:584-586, 1967.

2. Goodman, L., and A. Gilman, The Pharmacological Basis of

Thearpeutics, 6th ed., McGraw Hill, New York, p. 1005, 1980.

3. McConnell, T. H., ``Fatal Hypocalcemia from Phosphate

Absorption from Laxative Preparation,'' The Journal of the American

Medical Association, 216:147-148, 1971.

4. Korzets, A. et al., ``Life-Threatening Hyperphosphatemia and

Hypocalcemic Tetany Following the Use of Fleet Enemas,'' Journal of

the American Geriatric Society, 40:620-621, 1992.

5. Grosskopf, I. et al., ``Hyperphosphataemia and Hypocalcaemia

Induced by Hypertonic Phosphate Enema--An Experimental Study and

Review of the Literature,'' Human and Experimental Toxicology,

10:351-355, 1991.

6. Biberstein, M., and B. A. Parker, ``Enema-Induced

Hyperphosphatemia,'' The American Journal of Medicine, 79:645-646,

1985.

7. 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.

8. Wiberg, J. J., G. G. Turner, and F. Q. Nuttall, ``Effect of

Phosphate or Magnesium Cathartics on Serum Calcium,'' Archives of

Internal Medicine, 138:1114-1116, 1978.

9. Gilman, A. et al., The Pharmacological Basis of Therapeutics,

8th ed., Pergamon Press, New York, p. 919, 1992.

10. Martin, R. R. et al., ``Fatal Poisoning from Sodium

Phosphate Enema--Case Report and Experimental Study,'' The Journal

of the American Medical Association, 257:2190-2192, 1987.

11. 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.

12. 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.

13. Cagir, B. et al., ``Hypocalcemia in Surgical Critical Care

Patients: Measurements of Ionized Calcium,'' Contemporary Surgery,

45:71-78, 1994.

14. Rohack, J. J., B. R. Mehta, and K. Subramanyam,

``Hyperphosphatemia and Hypocalcemic Coma Associated with Phosphate

Enema,'' Southern Medical Journal, 78:1241-1242, 1985.

15. Edmondson, S., and T. D. Almquist, ``Iatrogenic Hypocalcemic

Tetany,'' Annals of Emergency Medicine, 19:938-940, 1990.

16. Sotos, J. F. et al., ``Hypocalcemic Coma Following Two

Pediatric Phosphate Enemas,'' Pediatrics, 60:305-307, 1977.

17. Spinrad, S. et al., ``Treating Constipation with Phosphate

Enema: An Unnecessary Risk,'' Israel Journal of Medical Sciences,

25:237-238, 1989.

18. Schuchmann, G. D., and P. J. Barcia, ``Phosphate Absorption

from Fleet Enemas in Adults,'' Current Surgery, 46:120-122, 1989.

19. Sweeney, J. L. et al., ``Rectal Gangrene: A Complication of

Phosphate Enema,'' Medical Journal of Australia, 144:374-375, 1986.

20. Saltzstein, R. J., E. Quebbeman, and J. L. Melvin,

``Anorectal Injuries Incident to Enema Administration. A Recurring

Avoidable Problem,'' American Journal of Physical Medical and

Rehabilitation, 67:186-188, 1988.

21. Honig, P. J., and P. G. Holtzapple, ``Hypocalcemic Tetany

Following Hypertonic Phosphate Enemas,'' Clinical Pediatrics,

14:678-679, 1975.

22. Hunter, F. M. et al., ``Hyperphosphataemia after Enemas in

Childhood: Prevention and Treatment,'' Archives of Diseases in

Childhood, 68:233-234, 1993.

23. Turell, R., ``Laceration to Anorectum Incident to Enema,''

Archives of Surgery, 81:953-954, 1960.

24. Bell, A. M., ``Colonic Perforation with a Phosphate Enema,''

Journal of the Royal Society of Medicine, 83:54-55, 1990.

25. Peitsch, J. B., H. M. Shizgal, and J. L. Meakins, ``Injury

by Hypertonic Phosphate Enema,'' Canadian Medical Association

Journal, 116:1169-1170, 1977.

26. Hool, G. J., E. L. Bokey, and M. T. Pheils, ``Enema-Nozzle

Injury of the Rectum,'' The Medical Journal of Australia, 1:364 and

381, 1980.

27. 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. 1928, 1994, OTC Vol. 090TFM4, Docket No. 78N-036L,

Dockets Management Branch.

28. Page, S. G., C. R. Riley, and H. B. Haag, ``A Comparative

Clinical Study of Several Enemas,'' The Journal of the American

Medical Association, 157:1208-1210, 1955.

29. Stempien, S. J., ``Double-Blind Evaluation of Sorbitol,

Phosphate, and Dextrose Enemas at Sigmoidoscopy,'' Gastroenterology,

36:830-831, 1959.

30. Bodi, T., and G. H. Frey, ``Clinical Evaluations of Small-

Volume Enemas,'' Pennsylvania Medical Journal, 68:35-38, 1965.

31. Weiss, Y., P. Grunberger, and S. Aronowitz, ``Asymptomatic

Rectal Perforation with Retroperitoneal Emphysema,'' American

Society of Colon and Rectal Surgeons, 24:545-547, 1980.

32. OTC Vol. 090011.

33. Labeling for Fleet Phospho-Soda, in OTC Vol. 090TFM3, Docket

No. 78N-036L, Dockets Management Branch.

IV. Summary of the Agency's Proposal for OTC Laxative Drug Products

Containing Sodium Phosphates

Based on new information, the agency is proposing changes in the

labeling for oral and rectal sodium phosphates drug products. A summary

of the changes proposed in this document follows.

1. The agency is revising proposed Sec. 334.16(d), (e), and (f) of

the monograph to use the current USP names for dibasic sodium

phosphate/monobasic sodium phosphate (sodium phosphates) drug products.

(See section I of this document.)

2. The agency is revising the warning proposed in

Sec. 334.58(c)(2)(ii) for

[[Page 27891]]

products containing oral sodium phosphates identified in

Sec. 334.16(d), (e), and (f) to state: ``Do not give to children under

6 years of age, without asking a doctor.''(See section II.C of this

document.)

3. The agency is revising the directions for oral sodium phosphates

in new Sec. 201.307(b)(3)(ii) (designated as Sec. 334.58(d)(5)(i) in

this proposal) and in proposed Sec. 334.58(d)(6) and (d)(7) to be

consistent with other oral OTC laxative drug products. The directions

will include oral dosages for children 6 years of age and older and

state to ask a doctor for children under 6 years of age. (See section

II.D of this document.)

4. The agency is changing the ``time to effect'' statement proposed

in Sec. 334.58(b)(2) for rectal dosage forms of sodium phosphates from

2 to 15 minutes to 1 to 5 minutes. (See section II.E of this document.)

5. The agency is expanding the warning for oral and rectal sodium

phosphates proposed in Sec. 334.58(c)(2)(i) to state: ``Do not use if''

(these four words in bold print) ``you have kidney disease, heart

problems, or are dehydrated, or for more than 3 days, without asking a

doctor.'' (See section II.C of this document.)

6. The agency is revising the warning proposed for rectal dosage

forms of sodium phosphates in Sec. 334.58(c)(2)(iii) which stated, ``Do

not give to children under 2 years of age unless directed by a

doctor,'' to read: ``Do not use in children under 2 years of age.'' The

agency is also revising the direction proposed for rectal sodium

phosphates in Sec. 334.58(d)(5)(ii) which stated, ``Children under 2

years of age: consult a doctor,'' with a new direction in

Sec. 334.58(d)(5)(ii)(A) that states: ``Do not use in children under 2

years of age.'' (See section II.C of this document.)

7. The agency is proposing new directions for rectal dosage forms

of sodium phosphates in Sec. 334.58(d)(5)(ii)(B) that state: ``If no

urge is felt after 5 minutes of using, try to empty bowel. Call a

doctor promptly if no liquid comes out of the rectum after 30 minutes

because dehydration could occur.'' (See section II.D of this document.)

8. The agency is proposing new directions in

Sec. 334.58(d)(5)(ii)(C) for rectal dosage forms of sodium phosphates

that state: ``Stop using if tip is hard to insert. Forcing the tip into

the rectum can cause injury (especially if you have hemorrhoids). If

enema tip causes rectal bleeding or pain, get immediate medical care.''

(See section II.D of this document.)

9. The agency is revising the professional labeling for oral and

rectal sodium phosphates proposed in Sec. 334.80(b)(2) to include

additional ``Do not use'' and ``Use with caution'' warnings. The agency

is also including new information about monitoring electrolytes and

treating electrolyte imbalances. The new warnings and other information

appear in Sec. 334.80(b)(2)(i) and (b)(2)(ii). (See section II.B of

this document.)

10. The agency has made an effort to shorten and simplify some of

the labeling, e.g., by using the phrase ``without asking a doctor''

instead of ``unless directed by a doctor.'' The agency has also

proposed a new format for professional labeling. The agency believes

that these changes will provide a clear and readable format for these

labeling statements. FDA is inviting specific comments on this labeling

format and on the wording of these statements.

V. Analysis of Impacts

FDA has examined the impacts of the proposed 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 would 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 1 year by State, local, and tribal governments, in the aggregate,

or by the private sector, of $100 million (adjusted annually for

inflation).

The agency believes that this proposed rule is consistent with the

principles set out in the Executive Order and in these two statutes.

The purpose of this proposed rule is to add warning and direction

statements to the general OTC and health professional (for health

professionals only) labeling of oral and rectal OTC sodium phosphates

drug products. These 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, and health professionals

recommend, these products.

The agency has been informed that relabeling costs of the type

required by this proposed rule (changes to both consumer and

professional labeling) generally average about $3,000 to $4,000 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 $390,000 to $520,000.

The agency also believes that actual costs 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, labeling changes would not be required until the

final monograph for OTC laxative drug products is issued and becomes

effective. The agency is proposing a 12-month implementation period

that would allow the manufacturers to coordinate these changes with

routinely scheduled label printing and/or other revisions required by

the final monograph for OTC laxative drug products. Thus, relabeling

costs for these products would be mitigated or reduced by the cost of

other labeling changes that the final monograph will also require.

The proposed 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 proposed rule.

The agency considered but rejected several labeling alternatives:

(1) Voluntary relabeling, (2) publication of the labeling information

in the FDA Drug Bulletin or professional journals, and (3) an exemption

from coverage for small entities. The agency does not consider the

first or third alternative 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 phosphates drug

products. The agency considers the second alternative useful and may

proceed with such publications. However, such publications do not

provide a permanent labeling requirement, which

[[Page 27892]]

the agency considers necessary for these products.

This proposed rule may have a significant economic impact on the

manufacturers of these products, all of which are considered to be

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 is also

likely to be a small entity. These manufacturers will need to change

the information panel of each affected sodium phosphates SKU and print

new professional labeling. Among the steps the agency is taking to

minimize the impact on these small entities are: (1) To provide 1 year

for implementation to enable entities to use up existing labeling

stock, and (2) to allow these labeling changes to be coordinated with

other labeling changes required by the final monograph. The agency

believes that these actions should help reduce the relabeling cost for

small entities.

The agency considered but rejected both a shorter and a longer

implementation period. While the agency would like to have this new

labeling in place as soon as possible, it considers a period less than

1 year difficult for manufacturers to implement all of the labeling

required by the final monograph. The agency considered a longer

effective date but finds it unacceptable 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. Manufacturers are encouraged to implement the new

labeling as soon as possible after the final monograph is published.

The analysis shows that this proposed 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 initial regulatory flexibility analysis, as required under the

Regulatory Flexibility Act. Finally, this analysis shows that the

Unfunded Mandates Act does not apply to the proposed rule because it

would 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 invites public comment regarding any substantial or

significant economic impact that this rulemaking would have on OTC

laxative drug products containing sodium phosphates. Comments regarding

the impact of this rulemaking on OTC laxative drug products containing

sodium phosphates should be accompanied by appropriate documentation.

The agency is providing a period of 90 days from the date of

publication of this proposed rulemaking in the Federal Register for

development and submission of comments on this subject. The agency will

evaluate any comments and supporting data that are received and will

reassess the economic impact of this rulemaking in the preamble to the

final rule.

VI. Paperwork Reduction Act of 1995

FDA tentatively concludes that the labeling requirements proposed

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 proposed labeling statements are a ``public

disclosure of information originally supplied by the Federal government

to the recipient for the purpose of disclosure to the public'' (5 CFR

1320.3(c)(2)).

VII. 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.

VIII. Request for Comments

Interested persons may, on or before August 19, 1998, submit

written comments or objections on the proposed regulation to the

Dockets Management Branch (address above). Three copies of all comments

or objections are to be submitted, except that individuals may submit

one copy. Comments should be identified with the docket number found in

brackets in the heading of this document and may be accompanied by a

supporting memorandum or brief. Received comments and objections may be

seen in the office above between 9 a.m. and 4 p.m., Monday through

Friday.

FDA is proposing that any final rule based on this proposal be

effective 12 months after the date of its publication in the Federal

Register.

List of Subjects in 21 CFR Part 334

Labeling, Over-the-counter drugs.

Therefore, under the Federal Food, Drug, and Cosmetic Act and under

authority delegated to the Commissioner of Food and Drugs, it is

proposed that 21 CFR part 334 (proposed in the Federal Register of

January 15, 1985, 50 FR 2124) be amended as follows:

PART 334--LAXATIVE DRUG PRODUCTS FOR OVER-THE-COUNTER HUMAN USE

1. The authority citation for 21 CFR part 334 continues to read as

follows:

Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371.

2. Section 334.16 is amended by revising paragraphs (d), (e), and

(f) to read as follows:

Sec. 334.16 Saline laxative active ingredients.

* * * * *

(d) Dibasic sodium phosphate/monobasic sodium phosphatemarketed as

a solution.

(e) Dibasic sodium phosphate.

(f) Monobasic sodium phosphate.

3. Section 334.58 is amended by revising paragraph (b)(2), by

revising paragraph (c)(2), by revising the heading of paragraph (d)(5)

and text of paragraph (d)(5)(i), by redesignating paragraph (d)(5)(ii)

as (d)(5)(ii)(A) and revising new (d)(5)(ii)(A), by adding new

paragraphs (d)(5)(ii)(B) and (d)(5)(ii)(C), and by revising the

headings and text of paragraphs (d)(6) and (d)(7) to read as follows:

Sec. 334.58 Labeling of saline laxative drug products.

* * * * *

(b) * * *

(2) Rectal dosage forms. ``This product generally produces bowel

movement in 1 to 5 minutes.''

(c) * * *

(2) For products containing dibasic sodium phosphate or monobasic

sodium phosphate identified in Sec. 334.16(d), (e), or (f)--(i) ``Do

not use if'' (these four words in bold print) ``you have kidney

disease, heart problems, or are dehydrated, or for more than 3 days,

without asking a doctor.''

(ii) Oral dosage forms. ``Do not give to children 5 years of age

and under, without asking a doctor.''

(iii) Rectal dosage forms. ``Do not use in children under 2 years

of age.''

(d) * * *

(5) For products containing dibasic sodium phosphate/ monobasic

sodium phosphate identified in Sec. 334.16(d) and marketed as a

solution--(i) Oral dosage. Adults and children 12 years of age and

over: Oral dosage is dibasic sodium phosphate 3.42 to 7.56 grams and

monobasic sodium phosphate 9.1 to 20.2 grams (20 to 45 milliliters (mL)

[[Page 27893]]

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 grams and

monobasic sodium phosphate 4.5 to 10.1 grams (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 6 to 9 years of age: Oral dosage is dibasic sodium

phosphate 0.86 to 1.89 gram and monobasic sodium phosphate 2.2 to 5.05

grams (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 6 years of age: ask

a doctor.

(ii) Rectal enema dosage. (A) Adults and children 12 years of age

and over: Enema dosage is dibasic sodium phosphate 6.84 to 7.56 grams

and monobasic sodium phosphate 18.24 to 20.16 grams in a single daily

dose. Children 2 to 11 years of age: Enema dosage is dibasic sodium

phosphate 3.42 to 3.78 grams and monobasic sodium phosphate 9.12 to

10.08 grams in a single daily dose. ``Do not use in children under 2

years of age.'' (Manufacturers should convert these dosages to the

amount of solution to be used.)

(B) ``If no urge is felt after 5 minutes of using, try to empty

bowel. Call a doctor promptly if no liquid comes out of the rectum

after 30 minutes because dehydration could occur.''

(C) ``Stop using if tip is hard to insert. Forcing the tip into the

rectum can cause injury (especially if you have hemorrhoids). If enema

tip causes rectal bleeding or pain, get immediate medical care.''

(6) For products containing dibasic sodium phosphate identified in

Sec. 334.16(e). Adults and children 12 years of age and over: Oral

dosage is 3.42 to 7.56 grams in a single daily dose. Children 10 to 11

years of age: Oral dosage is 1.71 to 3.78 grams in a single daily dose.

Children 6 to 9 years of age: Oral dosage is 0.86 to 1.89 gram in a

single daily dose. Children under 6 years of age: ask a doctor.

(7) For products containing monobasic sodium phosphate identified

in Sec. 334.16(f). Adults and children 12 years of age and over: Oral

dosage is 4.5 to 20.2 grams in a single daily dose. Children 10 to 11

years of ages: Oral dosage is 2.25 to 10.1 grams in a single daily

dose. Children 6 to 9 years of age: Oral dosage is 1.12 to 5.05 grams

in a single daily dose. Children under 6 years of age: ask a doctor.

4. Section 334.80 is amended by redesignating paragraph (b)(2) as

paragraph (b)(2)(i) and revising it, and by adding paragraph

(b)(2)(ii), to read as follows.

Sec. 334.80 Professional labeling.

* * * * *

(b) * * *

(2) For products containing dibasic sodium phosphate or monobasic

sodium phosphate identified in Sec. 334.16(d), (e), or (f)--(i) Oral

and rectal dosage forms--(A) ``Do not use'' (these three words in bold

print) ``in patients with congestive heart failure.''

(B) ``Use with caution'' (these three words in bold print) ``in

patients with impaired renal function, heart disease, acute myocardial

infarction, unstable angina, preexisting electrolyte disturbances (such

as dehydration or those secondary to the use of diuretics), the

elderly, or people taking drugs that may affect electrolyte levels.''

(C) ``Monitor electrolytes.'' (these two words in bold print)

``Give sufficient fluid replacement with all oral and rectal sodium

phosphates products to prevent dehydration.''

(D) ``What can occur:'' (these three words in bold print)

``Hypocalcemia, hyperphosphatemia, hypernatremia, hypokalemia, and

acidosis. These conditions are more likely to occur when more than one

dose of sodium phosphates is given in a 24-hour period.''

(E) ``What you should do:'' (these four words in bold print)

``Advise people to follow recommended dose. Treatment of electrolyte

imbalance may require immediate medical intervention with appropriate

electrolyte and fluid replacement. (Some examples of references for

treatment of this condition are Fonkalsrud, E., and J. Keen,

`Hypernatremic Dehydration Hypertonic Enemas in Congenital Megacolon,'

The Journal of the American Medical Association, 199:584-586, 1967, and

Edmondson, S., and T. D. Almquist, `Iatrogenic Hypocalcemic Tetany,'

Annals of Emergency Medicine, 19:938-940, 1990.)''

(ii) Rectal dosage forms. (A) ``Do not use'' (these three words in

bold print) ``sodium phosphates enema in children under 2 years of age

or in patients with congenital megacolon or imperforate anus because of

the risk of hyperosmotic dehydration and hyperphosphatemia.''

(B) ``Stop using'' (these two words in bold print) ``if there is

resistance to the enema tip. Forcing the tip into the rectum can result

in a serious injury that requires immediate medical attention.''

(C) ``Use sodium phosphates enema with extreme caution'' (these

seven words in bold print) ``in patients with a colostomy or atonic

colon (because of the risk of hyperosmotic dehydration and

hyperphosphatemia) or with a rectal abnormality, such as hemorrhoids

(because sodium phosphates can cause serious damage to the rectal

mucosa if an enema tip injury occurs). Using more than one sodium

phosphates enema in a 24-hour period can cause serious electrolyte

problems.''

* * * * *

Dated: April 27, 1998.

William K. Hubbard,

Associate Commissioner for Policy Coordination.

[FR Doc. 98-12054 Filed 5-20-98; 8:45 am]

BILLING CODE 4160-01-F