[Federal Register Volume 63, Number 98 (Thursday, May 21, 1998)]
[Proposed Rules]
[Pages 27886-27893]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-12054]


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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