[Federal Register Volume 63, Number 98 (Thursday, May 21, 1998)]
[Rules and Regulations]
[Pages 27836-27844]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-12053]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 201
[Docket No. 78N-036L]
RIN 0910-AA01
Package Size Limitation for Sodium Phosphates Oral Solution and
Warning and Direction Statements for Oral and Rectal Sodium Phosphates
for Over-the-Counter Laxative Use
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is issuing a final rule
to limit the container size for sodium phosphates oral solution
(dibasic sodium phosphate/monobasic sodium phosphate oral solution) to
not greater than 90 milliliters (mL) (3 ounces (oz)) when used as an
over-the-counter (OTC) laxative drug product. FDA is limiting the
container size because of reports of deaths associated with an
overdosage of sodium phosphates oral solution when the product was
packaged in a larger-size container and a larger than intended dose was
ingested inadvertently. The agency is also requiring warning and
direction statements to inform consumers that exceeding the recommended
dose of oral and rectal sodium phosphates products in a 24-hour period
can be harmful. This final rule is part of the ongoing review of OTC
drug products conducted by FDA.
DATES: The regulation is effective June 22, 1998, however compliance
with
[[Page 27837]]
Sec. 201.307(b)(2) and (b)(3) is not mandatory until September 18,
1998.
FOR FURTHER INFORMATION CONTACT: Cheryl A. Turner, Center for Drug
Evaluation and Research (HFD-560), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-827-2222.
SUPPLEMENTARY INFORMATION:
I. Background
In the Federal Register of March 21, 1975 (40 FR 12902), FDA
published, under Sec. 330.10(a)(6) (21 CFR 330.10(a)(6)), an advance
notice of proposed rulemaking to establish a monograph for OTC
laxative, antidiarrheal, emetic, and antiemetic drug products, together
with the recommendations of the Advisory Review Panel on OTC Laxative,
Antidiarrheal, Emetic, and Antiemetic Drug Products (the Panel), which
was the Advisory Review Panel responsible for evaluating data on the
active ingredients in these classes. The Panel recommended monograph
status for phosphate salts, such as sodium phosphates oral solution (40
FR 12902 at 12940), but did not recommend any container size
limitations.
The agency's proposed regulation, in the form of a tentative final
monograph, for OTC laxative drug products was published in the Federal
Register of January 15, 1985 (50 FR 2124). The agency also proposed
monograph status for sodium phosphates oral solution (50 FR 2124 at
2152 and 2155), but did not recommend any container size limitations.
The agency proposed the following dosage for sodium phosphates oral
solution for adults and children 12 years of age and over: 3.42 to 7.56
grams (g) of dibasic sodium phosphate and 9.1 to 20.2 g of monobasic
sodium phosphate \1\ in a single daily dose. (See proposed
Sec. 334.58(d)(5)(i) (21 CFR 334.58(d)(5)(i)), 50 FR 2124 at 2155.) In
addition to its use as an OTC laxative for the relief of occasional
constipation, sodium phosphates oral solution \2\ is used as part of a
bowel cleansing regimen in preparing a patient for surgery or for
preparing the colon for x-ray or endoscopic examination. (See proposed
Sec. 334.80(a)(2), 50 FR 2124 at 2157.) Sodium phosphates oral solution
and sodium phosphates enema \3\, respectively, are the current United
States Pharmacopeia (USP) names for the oral and rectal dosage forms of
the combination of sodium phosphates ingredients.
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\1\ In the tentative final monograph for OTC laxative drug
products, published in the Federal Register of January 15, 1985 (50
FR 2124), and in the proposed rule for package size limitation for
OTC laxative drug products published in the Federal Register of
March 31, 1994 (59 FR 15139), the agency referred to dibasic sodium
phosphate as ``sodium phosphate,'' and monobasic sodium phosphate as
``sodium biphosphate.'' The current nomenclature in the USP
Dictionary of USAN and International Drug Names, 1997 is ``dibasic
sodium phosphate'' and ``monobasic sodium phosphate,'' respectively.
This final rule uses the current nomenclature.
\2\Sodium phosphates oral solution is the official name for a
solution of dibasic sodium phosphate and monobasic sodium phosphate
in the U.S. Pharmacopeia 23/National Formulary 18, 1995.
\3\ Sodium phosphates enema is the official name for a solution
of dibasic sodium phosphate and monobasic sodium phosphate in the
U.S. Pharmacopeia 23/National Formulary 18, 1995.
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In the Federal Register of March 31, 1994 (59 FR 15139), the agency
proposed to amend the tentative final monograph for OTC laxative drug
products to limit the OTC container size for sodium phosphates oral
solution to not greater than 90 mL. The agency also proposed a warning
for all oral and rectal dosage forms of sodium phosphates products to
inform consumers not to exceed the recommended dosage unless directed
by a doctor. Interested persons were invited to submit written comments
on the proposed regulation and on the agency's economic impact
determination by May 31, 1994.
In response to the proposal, two manufacturers of laxative drug
products submitted comments. Neither comment addressed the agency's
economic impact determination. Copies of these comments are on public
display in the Dockets Management Branch (HFA-305), Food and Drug
Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857.
Additional information that has come to the agency's attention since
publication of the proposal is also on public display in the Dockets
Management Branch.
In the proposal, the agency discussed its reasons for limiting the
package size for sodium phosphates oral solution (59 FR 15139). The
agency noted that the major trade product containing sodium phosphates
oral solution was marketed in 45-mL, 90-mL, and 240-mL bottles. The
purgative dose or dose used for colonoscopy is 45 mL. Because the
product was available in three sizes, the manufacturer's labeling
advised physicians to prescribe by volumes and not to prescribe by the
bottle and not to exceed the recommended dosage, as serious side
effects may occur. Despite this labeling, the multiple container sizes
available in the marketplace have caused consumer confusion and appear
to have been involved in several consumer deaths.
The agency determined that the OTC availability of the 240-mL
container of sodium phosphates oral solution creates a potential safety
risk, particularly for elderly persons who are likely to use the
product for bowel cleansing prior to surgery or a diagnostic procedure
involving the colon. Because of the reported cases of accidental
overdosing and the confusion that has occurred between 240-mL and 90-mL
container sizes, the agency proposed that the 240-mL size container of
sodium phosphates oral solution should no longer remain in the OTC
marketplace. In the interest of safety, the agency proposed to limit
the maximum OTC container size for this product to 90 mL.
The agency proposed to include the package size limitation and
warning in the monograph for OTC laxative drug products. However, that
monograph has not been finalized to date. Because of the potential
safety risk involved, the agency has decided to finalize both the
package size limitation and several new warning and direction
statements prior to completion of the final monograph for OTC laxative
drug products. The agency has decided to include this information in
part 201 (21 CFR part 201) at this time and to incorporate it into the
final monograph for OTC laxative drug products at a later date.
In the Federal Register of February 27, 1997 (62 FR 9024), FDA
proposed to establish a standardized format for the labeling of OTC
drug products. Until the proposal is finalized, manufacturers,
distributors, and packagers must comply with the final rule published
herein and all other currently applicable labeling regulations. The
agency will eventually use the final labeling rule to incorporate the
information included herein in part 201 into the final monograph for
OTC laxative drug products.
II. The Agency's Conclusions on the Comments
1. One comment stated that, according to the USP 22 (Ref. 1), the
current terminology for sodium phosphate is monobasic sodium phosphate
and for sodium biphosphate it is dibasic sodium phosphate. The comment
stated that the tentative final monograph should be amended
accordingly.
Under agency regulations in 21 CFR 299.4(e), the established name
of a drug is the current compendial name or the USAN (U.S. Adopted
Names Council) adopted name listed in the USP Dictionary of USAN and
International Drug Names. Both the U.S. Pharmacopeia 23/National
Formulary 18 (Ref. 2) and the USP Dictionary of USAN and International
Drug Names, 1997 (Ref. 3) list the current name for sodium phosphate as
``dibasic sodium phosphate,'' and for sodium
[[Page 27838]]
biphosphate as ``monobasic sodium phosphate.'' (See footnote 1, supra.)
It appears that the comment inadvertently reversed the names of the
ingredients.
2. One comment stated that the agency's proposal that the final
rule be effective 30 days after its publication in the Federal Register
is insufficient time. The comment argued that 30 days would not be
enough time for relabeling of its sodium phosphates products and
requested that the final rule be effective 120 days after its
publication in the Federal Register.
The agency is instituting a split effective date for this final
rule. Because of the potential serious safety risk involved, the agency
has determined that initial introduction or initial delivery for
introduction into interstate commerce of any container size of sodium
phosphates oral solution greater than 90 mL should cease as soon as
possible (within 30 days of this final rule). However, the agency
concurs with the comment that manufacturers need more than 30 days to
relabel these drug products and is granting the 120 days requested by
the comment. Because of the potential serious safety risks, the agency
has determined that manufacturers need to work promptly to relabel
their products. The agency is providing manufacturers the option to use
supplementary labeling (e.g., stick-on labeling) to add the new warning
and direction information to currently manufactured products not yet
introduced into interstate commerce or on package labeling that has not
yet been incorporated into the manufacturing process. If manufacturers
choose not to use stick-on labeling, they are encouraged to have new
labeling containing the new warning and direction information printed
as expeditiously as possible in the interest of safe use of these
products.
3. One comment stated that sodium phosphates oral solution should
not be marketed in packages containing more than 45 mL. The comment
argued that 45 mL of this product equals the ``single daily dose'' of
solution generally recognized as safe and effective for use as a
laxative and bowel cleansing agent in the tentative final monograph.
The comment provided data to show that taking more than this amount has
been shown to cause significant changes in blood levels of sodium,
potassium, phosphate, chloride, and calcium, thereby imposing a risk of
serious injury (Refs. 4, 5, and 6).
The agency does not agree with the comment that packages containing
more than 45 mL of sodium phosphates oral solution should not be
marketed. Problems that previously occurred involved confusion
resulting from the availability of a 240-mL container size (59 FR
15139). (In 1993, the manufacturer of the major trade product
containing this solution ceased manufacture and initiated a market
withdrawal of the 240-mL container size.) The oral solution is
currently marketed in 45-mL and 90-mL containers. The agency has not
received any reports that a one-time 90 mL dose has resulted in a death
or a serious adverse reaction requiring medical treatment.
The agency has reviewed the submitted data (Refs. 4, 5, and 6) and
agrees that taking more than 45 mL of sodium phosphates solution over a
10- to 12-hour period can result in significant changes in electrolytes
and may impose a risk of serious injury. (See comment 4 in section II
of this document.) Therefore, the agency is requiring specific warning
and direction statements to ensure that the correct dose is used and
that consumers do not use more than the recommended dose in a 24-hour
period. The agency proposed to amend the tentative final monograph for
OTC laxative drug products to include in Sec. 334.58(c)(2)(iv) the
following warning for oral and rectal dosage forms of sodium phosphates
products: ``Do not exceed recommended dose unless directed by a doctor.
Serious side effects many occur from excess dosage'' (59 FR 15139).
In this final rule, the agency is revising the proposed warning by
adding 24-hour dosing information and by simplifying the language. The
agency is also requiring separate warnings for oral and rectal enema
drug products. For oral sodium phosphates drug products, the new
warning states: ``Taking more than the recommended dose in 24 hours can
be harmful.'' For rectal sodium phosphates drug products, the new
warning states: ``Using more than one enema in 24 hours can be
harmful.'' Both warnings must be in boldface type and appear as the
first statement under the heading ``Warnings.'' (See comment 5 in
section II of this document.)
The agency is also adding new directions in boldface type
immediately preceding the dosage information, which state: ``Do not''
(``take'' or ``use'') ``more unless directed by a doctor. See
Warnings.'' (See comment 4 in section II of this document.) The new
directions appear in Sec. 201.307(b)(3)(i).
The agency notes that sodium phosphates oral solution is available
for general laxative use for relief of occasional constipation at a
single daily dose of 20 mL to 45 mL for adults and children 12 years of
age and over. Thus, a larger size container (90 mL) may be more
convenient for consumers to purchase and have available for future use.
The agency is also aware that the 45-mL and 90-mL container sizes are
often recommended and prescribed by physicians for bowel cleansing
prior to surgery and diagnostic procedures of the colon. Accordingly,
the agency is allowing the 90-mL container of sodium phosphates oral
solution to remain on the OTC market. However, in an effort to prevent
consumers from taking an entire 90-mL container in 1 day (24 hours),
the agency is adding additional statements in the directions in
Sec. 201.307(b)(3)(ii) to inform consumers how much of the oral
solution may be taken as a single daily dose and not to take more than
the recommended daily dose in a 24-hour period. The agency has also
revised the format for stating children's ages from that proposed in
Sec. 334.58(d)(5)(i) of the tentative final monograph (50 FR 2124 at
2155). The directions now state:
Adults and children 12 years of age and over: Oral dosage is
dibasic sodium phosphate 3.42 to 7.56 grams (g) and monobasic sodium
phosphate 9.1 to 20.2 g (20 to 45 mL dibasic sodium phosphate/
monobasic sodium phosphate oral solution) as a single daily dose.
``Do not take more than 45 mL (9 teaspoonfuls or 3 tablespoonfuls)
in a 24-hour period.''
Children 10 and 11 years of age: Oral dosage is dibasic sodium
phosphate 1.71 to 3.78 g and monobasic sodium phosphate 4.5 to 10.1
g (10 to 20 mL dibasic sodium phosphate/monobasic sodium phosphate
oral solution) as a single daily dose. ``Do not take more than 20 mL
(4 teaspoonfuls) in a 24-hour period.''
Children 5 to 9 years of age: Oral dosage is dibasic sodium
phosphate 0.86 to 1.89 g and monobasic sodium phosphate 2.2 to 5.05
g (5 to 10 mL dibasic sodium phosphate/monobasic sodium phosphate
oral solution) as a single daily dose. ``Do not take more than 10 mL
(2 teaspoonfuls) in a 24-hour period.'' Children under 5 years of
age: ask a doctor.
The agency notes that the directions for sodium phosphates oral
solution contain separate dosages for children 10 and 11 years of age
and for children 5 to 9 years of age. These age ranges are not
consistent with age ranges used for the majority of OTC laxative drug
products, which recommend dosages for children 6 to 11 years of age.
Therefore, elsewhere, in this issue of the Federal Register, the agency
is proposing to revise the directions for sodium phosphates oral
solution to limit the OTC use of these products to children 6 years of
age and above.
The proposed directions state:
* * * Children 6 to 9 years of age: Oral dosage is dibasic
sodium phosphate 0.86 to 1.89 g and monobasic sodium phosphate 2.2
to 5.05 g (5 to 10 mL dibasic sodium phosphate/monobasic sodium
phosphate oral
[[Page 27839]]
solution) as a single daily dose. `Do not take more than 10 mL (2
teaspoonfuls) in a 24-hour period.' Children under 6 years of age:
ask a doctor.
4. One comment requested that sodium phosphates oral solution
products bear a warning against consuming more than 45 mL in a 24-hour
period unless directed by a physician. The comment contended that there
are potentially serious health problems associated with high doses of
this product. The comment submitted data to show that consuming more
that 45 mL of sodium phosphates oral solution in 24 hours has resulted
in significant changes in blood levels of sodium, potassium, phosphate,
chloride, and calcium, thereby imposing a risk of serious injury (Refs.
4, 5, and 6).
The agency has reviewed the submitted data and agrees that
ingesting more that 45 mL of sodium phosphates oral solution in a 24-
hour period may be harmful. Clarkston et al. (Ref. 4) compared a
polyethylene glycol (PEG) based gastrointestinal lavage to a sodium
phosphates oral regimen. In this randomized trial, 26 subjects took 4
liters (L) of the PEG solution and 25 subjects took two 45-mL doses of
sodium phosphates oral solution 11 hours apart. The subjects had a
chemistry panel and ionized calcium done prior to taking the drug and
on the morning of the colonoscopy. The results indicated that the
sodium phosphates solution caused a decrease in ionized serum calcium
and serum potassium, with concomitant increases in phosphate. The
investigators stated that the sodium phosphates oral regimen resulted
in statistically significant changes in serum sodium, potassium,
phosphorus, and calcium (p < 0.01).="" the="" investigators="" concluded="" that="" the="" risk="" of="" symptoms="" of="" hypocalcemia="" must="" be="" considered="" due="" to="" the="" abnormal="" low="" levels="" of="" ionized="" calcium="" that="" frequently="" occur="" with="" this="" regimen.="" vanner="" et="" al.="" (ref.="" 5)="" compared="" a="" standard="" peg="" based="" gastrointestinal="" solution="" to="" a="" sodium="" phosphates="" oral="" solution="" prior="" to="" colonoscopy.="" in="" this="" parallel,="" single-blinded,="" randomized="" study,="" 54="" subjects="" received="" two="" 45-ml="" doses="" of="" the="" sodium="" phosphates="" oral="" solution="" 11="" hours="" apart,="" and="" 48="" subjects="" received="" 4="" l="" of="" the="" peg="" solution.="" the="" subjects="" had="" blood="" tests="" on="" admission="" and="" the="" morning="" of="" the="" procedure.="" the="" authors="" concluded="" that="" the="" sodium="" phosphates="" oral="" solution="" was="" safe="" and="" effective="" because="" serial="" measurements="" of="" blood="" tests,="" postural="" pulse,="" and="" blood="" pressure="" changes="" did="" not="" reveal="" any="" clinically="" significant="" changes="" in="" intravascular="" volume.="" one="" ``syncopal="" episode''="" occurred="" in="" the="" sodium="" phosphates="" group.="" the="" authors="" mentioned="" that="" the="" subject's="" vital="" signs="" did="" not="" appear="" to="" indicate="" that="" hypovolemia="" (abnormally="" decreased="" volume="" of="" circulating="" plasma)="" was="" the="" cause.="" the="" authors="" reported="" that="" hyperphosphatemia="" occurred="" with="" sodium="" phosphates,="" but="" serum="" phosphate="" values="" returned="" to="" normal="" within="" 24="" hours,="" and="" no="" concomitant="" decrease="" in="" calcium="" was="" seen.="" they="" added="" that="" histological="" assessment="" for="" possible="" preparation-induced="" changes="" revealed="" no="" difference="" between="" the="" two="" drugs.="" the="" agency="" notes="" that="" numerous="" induced="" electrolyte="" abnormalities="" occurred="" in="" this="" study.="" the="" data="" showed="" statistically="" significant="" decreases="" in="" potassium="" and="" increases="" in="" hematocrit,="" sodium,="" chloride,="" osmolality,="" and="" phosphate.="" extreme="" serum="" phosphate="" levels="" reached="" 11.6="" milligrams/deciliter="" (mg/dl)="" in="" the="" sodium="" phosphates="" group="" and="" 4.7="" mg/="" dl="" in="" the="" peg="" group;="" normal="" values="" are="" 2.5="" to="" 4.1="" mg/dl.="" in="" hyperphosphatemia,="" excessive="" complexing="" of="" calcium="" with="" phosphate="" may="" contribute="" to="" a="" decrease="" in="" plasma="" ionized="" calcium,="" which="" results="" in="" hypocalcemia.="" calcium="" levels="" were="" not="" reported="" for="" the="" entire="" sodium="" phosphates="" group="" nor="" was="" the="" risk="" of="" hypokalemia="" mentioned.="" the="" agency="" notes="" that="" the="" postural="" changes="" in="" pulse,="" systolic="" blood="" pressure,="" and="" the="" one="" ``syncopal="" episode''="" were="" most="" likely="" due="" to="" decreased="" intravascular="" volume="" in="" subjects="" in="" the="" sodium="" phosphates="" group.="" because="" elevated="" phosphate="" levels="" are="" known="" to="" occur="" with="" sodium="" phosphates="" use,="" 15="" subjects="" were="" randomly="" selected="" to="" have="" serum="" phosphate="" and="" calcium="" levels="" measured="" at="" 4="" p.m.="" on="" the="" day="" of="" colonoscopy="" and="" at="" 8="" a.m.="" the="" following="" day.="" seven="" of="" the="" fifteen="" subjects="" received="" the="" sodium="" phosphates="" regimen.="" vanner="" et="" al.="" reported="" that="" 2="" hours="" after="" the="" second="" dose,="" the="" mean="" serum="" phosphorus="" was="" 7.2="" mg/dl="" (nearly="" twice="" the="" pre-study="" value="" of="" 3.7="" mg/dl),="" while="" the="" total="" calcium="" values="" continued="" to="" decline="" for="" at="" least="" 24="" hours="" after="" the="" dose="" was="" taken.="" the="" agency="" believes="" that="" the="" vanner="" et="" al.="" study="" showed="" that="" postural="" increases="" in="" pulse,="" decreases="" in="" systolic="" blood="" pressure,="" and="" serum="" electrolyte="" and="" plasma="" volume="" shifts="" were="" greater="" in="" the="" sodium="" phosphates="" group="" than="" in="" the="" peg="" group.="" the="" incidence="" of="" postural="" elevation="" in="" heart="" rate,="" indicating="" significant="" reduction="" in="" intravascular="" volume,="" was="" also="" three="" times="" higher="" in="" the="" sodium="" phosphates="" group="" than="" in="" the="" peg="" group.="" because="" of="" the="" small="" sample="" size,="" the="" fact="" that="" none="" of="" the="" study="" subjects="" died="" or="" had="" serious="" side="" effects="" that="" required="" hospitalization="" cannot="" be="" interpreted="" to="" mean="" that="" two="" 45-ml="" doses="" of="" sodium="" phosphates="" oral="" solution="" are="" safe="" to="" ingest="" without="" a="" physician's="" supervision.="" warner="" and="" dipalma="" (ref.="" 6)="" stated="" that="" sodium="" phosphates="" oral="" solution="" is="" extremely="" popular="" for="" use="" as="" a="" bowel="" cleansing="" agent="" because="" it="" is="" effective,="" easy="" to="" administer,="" and="" well="" tolerated.="" however,="" they="" contended="" that="" little="" data="" are="" available="" concerning="" its="" safety.="" they="" mentioned="" that="" the="" majority="" of="" trials="" evaluating="" the="" product="" for="" use="" as="" a="" bowel="" cleanser="" have="" not="" systematically="" monitored="" electrolytes.="" they="" asserted="" that="" the="" solubility="" product="" of="" calcium="" and="" phosphate,="" when="" exceeded,="" leads="" to="" soft="" tissue="" calcification="" in="" areas="" where="" an="" alkaline="" internal="" environment="" enhances="" calcium="" phosphate="" salt="" deposit,="" primarily="" in="" the="" kidneys,="" heart,="" blood="" vessel,="" cornea,="" lungs,="" and="" gastric="" mucosa.="" they="" stated="" that="" the="" normal="" calcium-phosphate="" product="" is="" 40="" mg/dl,="" which="" is="" tightly="" regulated="" through="" absorption,="" excretion,="" and="" intracellular/extracellular="" ion="" shifts;="" and="" that="" the="" in="" vitro="" solubility="" product="" of="" calcium="" is="" 58="" mg/dl,="" well="" above="" the="" normal="" value="" (ref.="" 6).="" warner="" and="" dipalma="" mentioned="" that="" vanner="" et="" al.="" (ref.="" 5)="" and="" kolts="" (ref.="" 7)="" have="" presented="" limited="" data="" to="" show="" phosphate="" levels="" rising="" to="" as="" high="" as="" 7="" mg/dl="" with="" relatively="" unchanged="" serum="" calcium="" values.="" according="" to="" warner="" and="" dipalma,="" the="" increase="" in="" phosphate="" levels="" appeared="" quite="" transient,="" but="" because="" sampling="" was="" so="" infrequent,="" it="" is="" impossible="" to="" ascertain="" whether="" even="" these="" high="" values="" represent="" the="" peak="" phosphate="" concentrations="" after="" administration="" of="" sodium="" phosphates="" oral="" solution.="" kolts="" (ref.="" 8)="" responded="" to="" warner="" and="" dipalma,="" and="" argued="" that="" sodium="" phosphates="" oral="" solution="" should="" be="" the="" preparation="" of="" choice="" for="" most="" endoscopy="" outpatients="" due="" to="" its="" low="" cost,="" comfort="" for="" the="" patient,="" and="" low="" incidence="" of="" adverse="" side="" events.="" kolts="" stated="" that="" the="" sodium="" phosphates="" oral="" solution="" used="" in="" his="" study="" (ref.="" 7)="" had="" been="" sold="" otc="" for="" more="" than="" 100="" years="" and="" the="" manufacturer="" had="" not="" reported="" any="" serious="" side="" effects,="" except="" when="" the="" solution="" was="" taken="" in="" massive="" overdoses="" or="" if="" used="" when="" contraindicated.="" kolts="" added="" that="" there="" were="" no="" reports="" of="" adverse="" events="" such="" as="" ectopic="" calcification="" in="" the="" literature="" from="" 1966="" to="" 1993="" from="" the="" use="" of="" phosphate="" catharsis="" in="" people="" with="" normal="" renal="" function.="" kolts="" concluded="" that="" his="" (ref.="" 7)="" and="" vanner's="" (ref.="" 5)="" studies="" documented="" the="" minor="" changes="" [[page="" 27840]]="" in="" clinically="" relevant="" electrolytes="" as="" well="" as="" the="" lack="" of="" adverse="" symptoms="" from="" sodium="" phosphates="" oral="" solution.="" the="" agency="" finds="" that="" the="" data="" show="" that="" sodium="" phosphates="" oral="" solution="" can="" cause="" alterations="" in="" serum="" levels="" of="" sodium,="" potassium,="" phosphate,="" chloride,="" and="" calcium.="" in="" some="" people,="" such="" changes="" can="" be="" life-threatening.="" the="" agency="" has="" particular="" concerns="" about="" hypocalcemia="" occurring="" due="" to="" its="" reported="" frequency="" when="" two="" 45-ml="" doses="" of="" sodium="" phosphates="" oral="" solution="" are="" given="" over="" a="" 24-hour="" period.="" the="" reduction="" of="" calcium="" levels="" reflects="" changes="" in="" ionized="" calcium="" (ref.="" 9).="" hypocalcemia="" with="" subsequent="" low="" levels="" of="" ionized="" calcium="" may="" result="" in="" neuromuscular="" irritability,="" heart="" block,="" and="" cardiovascular="" failure="" (ref.="" 9).="" in="" the="" tentative="" final="" monograph="" for="" otc="" laxative="" drug="" products="" (50="" fr="" 2124="" at="" 2155),="" the="" agency="" proposed="" a="" maximum="" single="" daily="" oral="" dose="" of="" 7.56="" g="" of="" dibasic="" sodium="" phosphate="" and="" 20.2="" g="" of="" monobasic="" sodium="" phosphate.="" the="" major="" manufacturer="" of="" sodium="" phosphates="" products="" recommends="" (as="" part="" of="" a="" bowel="" cleansing="" regimen="" in="" preparation="" for="" surgery="" or="" preparation="" of="" the="" colon="" for="" x-ray="" or="" endoscopic="" examination)="" (ref.="" 10)="" that="" 45="" ml="" be="" given="" at="" 7="" p.m.="" and="" again="" at="" 6="" a.m.="" the="" following="" morning.="" the="" agency="" notes="" that="" 0.9="" g/5="" ml="" of="" dibasic="" sodium="" phosphate="" is="" equivalent="" to="" 17.1="" to="" 18.9="" g/100="" ml="" of="" sodium="" phosphates="" oral="" solution,="" and="" that="" 2.4="" g/5="" ml="" of="" monobasic="" sodium="" phosphate="" is="" equivalent="" to="" 45.6="" to="" 50.4="" g/100="" ml="" of="" sodium="" phosphates="" oral="" solution="" according="" to="" the="" usp="" 23="" (ref.="" 2).="" therefore,="" over="" an="" 11-="" hour="" period,="" 90="" ml="" of="" solution="" (approximately="" 16.2="" g="" of="" dibasic="" sodium="" phosphate="" and="" 43.2="" g="" of="" monobasic="" sodium="" phosphate)="" containing="" 9.9="" g="" of="" sodium="" could="" be="" consumed.="" the="" manufacturer="" of="" this="" product="" has="" not="" submitted="" sufficient="" data="" to="" demonstrate="" the="" safety="" of="" more="" than="" 45="" ml="" of="" this="" solution="" in="" a="" 24-hour="" period="" (ref.="" 11).="" thus,="" the="" agency="" concludes="" that="" the="" safe="" oral="" use="" of="" more="" than="" 7.56="" g="" of="" dibasic="" sodium="" phosphate="" and="" 20.2="" g="" of="" monobasic="" sodium="" phosphate="" in="" a="" 24-hour="" period="" has="" not="" been="" demonstrated="" at="" this="" time.="" therefore,="" the="" agency="" will="" not="" include="" a="" greater="" dosage="" in="" a="" 24-hour="" period="" in="" the="" otc="" or="" professional="" labeling="" in="" the="" final="" monograph="" for="" otc="" laxative="" drug="" products,="" which="" will="" be="" published="" in="" a="" future="" issue="" of="" the="" federal="" register.="" the="" agency="" agrees="" with="" the="" comment="" that="" the="" labeling="" for="" sodium="" phosphates="" oral="" solution="" should="" include="" a="" warning="" not="" to="" ingest="" more="" than="" the="" recommended="" dose="" in="" a="" 24-hour="" period.="" accordingly,="" the="" agency="" is="" including="" the="" following="" warning="" in="" sec.="" 201.307(b)(2)(i)="" for="" oral="" products="" that="" contain="" sodium="" phosphates:="" ``taking="" more="" than="" the="" recommended="" dose="" in="" 24="" hours="" can="" be="" harmful.''="" the="" sentence="" is="" required="" to="" appear="" in="" boldface="" type="" as="" the="" first="" statement="" under="" the="" heading="" ``warnings.''="" the="" agency="" is="" also="" requiring="" in="" sec.="" 201.307(b)(3)(i)="" that="" the="" directions="" for="" oral="" and="" rectal="" sodium="" phosphates="" products="" contain="" the="" following="" statements="" in="" boldface="" type="" immediately="" preceding="" the="" dosage="" information:="" ``do="" not''="" (``take''="" or="" ``use'')="" ``more="" unless="" directed="" by="" a="" doctor.="" see="" warnings.''="" (see="" comment="" 5="" in="" section="" ii="" of="" this="" document.)="" these="" additional="" statements="" are="" intended="" to="" refer="" consumers="" to="" the="" warnings="" when="" they="" read="" the="" directions="" for="" the="" product.="" 5.="" one="" comment="" disagreed="" with="" the="" proposed="" warning="" in="" sec.="" 334.58(c)(2)(iv)="" for="" rectal="" enema="" sodium="" phosphates="" drug="" products,="" which="" states:="" ``do="" not="" exceed="" recommended="" dose="" unless="" directed="" by="" a="" doctor.="" serious="" side="" effects="" may="" occur="" from="" excess="" dosage.''="" the="" comment="" argued="" that="" the="" agency="" provided="" no="" concrete="" or="" specific="" evidence="" to="" support="" this="" warning.="" the="" comment="" stated="" that="" its="" sodium="" phosphates="" enema="" contains="" 19="" g/118="" ml="" (equivalent="" to="" 16="" g/100="" ml)="" of="" monobasic="" sodium="" phosphate="" and="" 7="" g/118="" ml="" (equivalent="" to="" 7="" g/100="" ml)="" of="" dibasic="" sodium="" phosphate.="" in="" contrast,="" the="" oral="" product="" contains="" 2.4="" g/="" 5="" ml="" (equivalent="" to="" 48="" g/100="" ml)="" of="" monobasic="" sodium="" phosphate="" and="" 0.9="" g/5="" ml="" (equivalent="" to="" 18="" g/100="" ml)="" of="" dibasic="" sodium="" phosphate.="" the="" comment="" stated="" that="" because="" the="" phosphate="" concentration="" of="" the="" enema="" is="" only="" one-third="" that="" of="" the="" oral="" product,="" use="" of="" the="" enema="" is="" not="" likely="" to="" result="" in="" overdosage.="" the="" comment="" added="" that="" an="" overdosage="" is="" unlikely="" to="" occur="" due="" to="" the="" way="" enemas="" are="" used="" and="" the="" results="" they="" produce.="" the="" comment="" mentioned="" that="" the="" enema="" product="" is="" clearly="" labeled="" ``not="" intended="" for="" oral="" consumption,''="" and="" that="" the="" current="" labeling="" clearly="" states="" the="" appropriate="" dosage.="" thus,="" the="" comment="" concluded="" that="" the="" warning="" should="" not="" be="" required="" for="" sodium="" phosphates="" enema="" products.="" another="" comment="" stated="" that="" the="" dosage="" and="" administration="" section="" of="" products="" containing="" sodium="" phosphates="" should="" be="" allowed="" to="" contain="" statements="" similar="" to="" the="" following="" proposed="" warning:="" ``do="" not="" exceed="" recommended="" dose="" unless="" directed="" by="" a="" doctor.="" serious="" side="" effects="" may="" occur="" from="" excess="" dosage.''="" the="" comment="" indicated="" that="" such="" statements="" should="" be="" allowed,="" but="" do="" not="" need="" to="" be="" included="" in="" the="" final="" rule.="" the="" agency="" notes="" that="" the="" first="" comment="" made="" an="" error="" in="" its="" statement="" of="" the="" amount="" of="" dibasic="" sodium="" phosphate="" per="" 100="" ml.="" it="" should="" have="" been="" approximately="" 6="" g/ml="" which="" is="" consistent="" with="" usp="" 23="" (ref.="" 2),="" which="" states="" that="" each="" 100="" ml="" of="" sodium="" phosphates="" enema="" solution="" contains="" not="" less="" than="" 5.7="" g="" and="" not="" more="" than="" 6.3="" g="" of="" dibasic="" sodium="" phosphate.="" the="" agency="" is="" aware="" of="" numerous="" reports="" of="" misuse="" of="" sodium="" phosphates="" enemas="" that="" resulted="" in="" adverse="" effects="" (refs.="" 12="" through="" 23).="" wason="" et="" al.="" (ref.="" 12)="" reported="" the="" case="" of="" a="" normal="" 5-month-old="" child="" who="" was="" given="" an="" entire="" adult="" sodium="" phosphates="" enema="" by="" her="" mother.="" within="" 30="" minutes,="" the="" child="" became="" extremely="" ill;="" consciousness="" decreased;="" and="" shock,="" hyperphosphatemia,="" hypocalcemia,="" and="" acidosis="" developed.="" the="" child="" was="" hospitalized="" and="" responded="" to="" intravenous="" (iv)="" fluid="" replacement="" and="" aluminum="" hydroxide="" gel.="" oxnard,="" o'bell,="" and="" grupe="" (ref.="" 13)="" reported="" that="" a="" 4-year-old="" child="" with="" chronic="" renal="" failure="" became="" profoundly="" hyperphosphatemic="" and="" hypocalcemic="" after="" receiving="" an="" entire="" adult="" sodium="" phosphates="" enema.="" the="" child="" developed="" muscle="" twitching,="" acidosis,="" severe="" diarrhea,="" and="" tachycardia,="" and="" was="" hospitalized,="" subsequently="" responding="" to="" iv="" calcium="" gluconate,="" calcium="" chloride,="" and="" sodium="" bicarbonate.="" other="" authors="" have="" reported="" that="" children="" (4="" months="" to="" 2="" 1/2="" years="" old)="" with="" gastrointestinal="" anomalies,="" such="" as="" hirschsprung's="" disease="" (congenital="" megacolon),="" and="" chronic="" renal="" failure="" were="" at="" high="" risk="" for="" complications="" after="" the="" use="" of="" sodium="" phosphates="" enemas="" (refs.="" 13="" through="" 20).="" these="" children="" received="" varying="" amounts="" of="" adult="" or="" pediatric="" sodium="" phosphates="" enemas="" for="" constipation="" and="" bowel="" cleansing="" prior="" to="" surgery.="" three="" of="" the="" children="" had="" cardiac="" arrest="" after="" the="" use="" of="" hypertonic="" sodium="" phosphates="" enemas="" (refs.="" 17,="" 19,="" and="" 20).="" martin="" et="" al.="" (ref.="" 19)="" reported="" that="" an="" 11-month-old="" child="" died="" after="" receiving="" four="" adult="" sodium="" phosphates="" enemas.="" loughnan="" and="" mullins="" (ref.="" 17)="" reported="" that="" a="" 9-month-old="" child="" suffered="" severe="" and="" permanent="" brain="" damage="" after="" receiving="" a="" pediatric="" sodium="" phosphates="" enema.="" reedy="" and="" zwiren="" (ref.="" 20)="" reported="" that="" a="" 17-month-old="" child="" received="" two="" pediatric="" sodium="" phosphates="" enemas="" as="" a="" ``bowel="" prep''="" on="" the="" day="" of="" surgery="" and="" was="" successfully="" resuscitated="" after="" experiencing="" cardiac="" arrest="" during="" induction="" of="" anesthesia.="" the="" authors="" noted="" that="" the="" child="" had="" received="" sodium="" phosphates="" enemas="" chronically="" but="" that="" a="" possible="" electrolyte="" imbalance="" was="" not="" suspected,="" and="" the="" child="" was="" not="" screened="" for="" any="" possible="" electrolyte="" problems="" prior="" to="" surgery.="" [[page="" 27841]]="" other="" authors="" (refs.="" 21,="" 22,="" and="" 23)="" have="" reported="" acidosis,="" hypocalcemia,="" and="" hyperphosphatemia="" that="" occurred="" in="" adults="" and="" children="" after="" the="" use="" of="" sodium="" phosphates="" enema="" products.="" davis="" et="" al.="" (ref.="" 21)="" state="" that="" these="" products="" can="" cause="" electrolyte="" imbalances,="" which="" can="" cause="" severe="" reactions="" and="" could="" result="" in="" death,="" when="" administered="" in="" the="" recommended="" doses="" to="" individuals="" with="" normal="" renal="" function.="" the="" agency="" is="" also="" aware="" of="" serious="" electrolyte="" imbalances="" occurring="" in="" individuals="" who="" used="" more="" than="" one="" sodium="" phosphates="" enema="" in="" a="" 24-hour="" period="" (refs.="" 15,="" 16,="" 24,="" 25,="" and="" 26).="" thus,="" an="" electrolyte="" imbalance="" can="" result="" from="" an="" excess="" dose="" of="" either="" the="" oral="" solution="" or="" the="" enema="" dosage="" form.="" because="" of="" the="" serious="" side="" effects="" that="" can="" occur="" from="" overdosage,="" the="" agency="" considers="" it="" important="" to="" include="" information="" against="" exceeding="" the="" recommended="" dose="" of="" sodium="" phosphates="" drug="" products="" in="" both="" the="" warnings="" and="" directions="" sections="" of="" product="" labeling.="" the="" agency="" concludes="" that="" this="" information="" needs="" to="" be="" required,="" not="" just="" voluntarily="" included="" at="" a="" manufacturer's="" discretion.="" iii.="" references="" the="" following="" references="" are="" on="" display="" in="" the="" dockets="" management="" branch="" (address="" above)="" and="" may="" be="" seen="" by="" interested="" persons="" between="" 9="" a.m.="" and="" 4="" p.m.,="" monday="" through="" friday.="" 1.="" the="" united="" stated="" pharmacopeia="" 22/="" the="" national="" formulary="" 17,="" the="" united="" states="" pharmacopeial="" convention="" inc.,="" rockville,="" md,="" pp.="" 1265-1267,="" 1989.="" 2.="" the="" united="" states="" pharmacopeia="" 23/="" the="" national="" formulary="" 18,="" the="" united="" states="" pharmacopeial="" convention="" inc.,="" rockville,="" md,="" pp.="" 1428-1430,="" 1994.="" 3.="" united="" states="" pharmacopeia="" dictionary="" of="" united="" states="" adopted="" names="" and="" international="" drug="" names,="" the="" united="" states="" pharmacopeial="" convention="" inc.,="" rockville,="" md,="" p.="" 658,="" 1997.="" 4.="" clarkston,="" w.="" k.="" et="" al.,="" ``a="" single="" blind="" comparison="" of="" serum="" electrolytes,="" serum="" phosphorus,="" serum="" calcium,="" and="" ventricular="" arrhythmias="" in="" outpatients="" receiving="" nulytely="" versus="" fleet="" phospho-="" soda="" preparation="" for="" colonoscopy:="" preliminary="" results="" (unpublished="" study),''="" pp.="" 1-28,="" 1994,="" otc="" vol.="" 090tfm4,="" docket="" no.="" 78n-036l,="" dockets="" management="" branch.="" 5.="" vanner,="" s.="" j.="" et="" al.,="" ``a="" randomized="" prospective="" trial="" comparing="" oral="" sodium="" phosphate="" with="" standard="" polyethylene="" glycol-="" based="" lavage="" solution="" (golytely)="" in="" the="" preparation="" of="" patients="" for="" colonoscopy,''="" the="" american="" journal="" of="" gastroenterology,="" 85:422-427,="" 1990.="" 6.="" warner,="" b.="" a.,="" and="" j.="" a.="" dipalma,="" ``oral="" sodium="" phosphate="" catharsis:="" `first="" do="" no="" harm',''="" the="" american="" journal="" of="" gastroenterology,="" 89:1118-1119,="" 1994.="" 7.="" kolts,="" b.="" e.="" et="" al.,="" ``a="" comparison="" of="" the="" effectiveness="" and="" patient="" tolerance="" of="" oral="" sodium="" phosphate,="" castor="" oil,="" and="" standard="" electrolyte="" lavage="" for="" colonoscopy="" or="" sigmoidoscopy="" preparation,''="" the="" american="" journal="" of="" gastroenterology,="" 88:1218-1223,="" 1993.="" 8.="" kolts,="" b.="" e.,="" ``response="" to="" drs.="" warner="" and="" dipalma,''="" the="" american="" journal="" of="" gastroenterology,="" 89:1119,="" 1994.="" 9.="" cagir,="" b.="" et="" al.,="" ``hypocalcemia="" in="" surgical="" critical="" care="" patients:="" measurements="" of="" ionized="" calcium,''="" contemporary="" surgery,="" 45:71-78,="" 1994.="" 10.="" physicians'="" desk="" reference,="" 50th="" ed.,="" medical="" economics="" data="" production="" co.,="" montvale,="" nj,="" pp.="" 1002-1004,="" 1996.="" 11.="" letter="" from="" w.="" e.="" gilbertson,="" fda,="" to="" p.="" reichertz,="" arent,="" fox,="" kintner,="" plotkin="" &="" kahn,="" dated="" march="" 1,="" 1996,="" coded="" as="" let109,="" docket="" no.="" 78n-036l,="" dockets="" management="" branch.="" 12.="" wason,="" s.="" et="" al.,="" ``severe="" hyperphosphatemia,="" hypocalcemia,="" acidosis,="" and="" shock="" in="" a="" 5-month="" old="" child="" following="" the="" administration="" of="" an="" adult="" fleet="" enema,''="" annals="" of="" emergency="" medicine,="" 18:696-700,="" 1989.="" 13.="" oxnard,="" s.="" c.,="" j.="" o'bell,="" and="" w.e.="" grupe,="" ``severe="" tetany="" in="" an="" azotemic="" child="" related="" to="" a="" sodium="" phosphate="" enema,''="" pediatrics,="" 53:105-106,="" 1974.="" 14.="" chesney,="" r.="" w.,="" and="" p.="" b.="" haughton,="" ``tetany="" following="" phosphate="" enemas="" in="" chronic="" renal="" disease,''="" american="" journal="" of="" diseases="" of="" children,="" 127:584-586,="" 1974.="" 15.="" honig,="" p.="" j.,="" and="" p.="" g.="" holtzapple,="" ``hypocalcemic="" tetany="" following="" hypertonic="" phosphate="" enemas,''="" clinical="" pediatrics,="" 14:678-679,="" 1975.="" 16.="" sotos,="" j.="" f.="" et="" al.,="" ``hypocalcemic="" coma="" following="" two="" pediatric="" phosphate="" enemas,''="" american="" academy="" of="" pediatrics,="" 60:305-307,="" 1977.="" 17.="" loughnan,="" p.,="" and="" g.="" c.="" mullins,="" ``brain="" damage="" following="" a="" hypertonic="" phosphate="" enema,''="" american="" journal="" of="" diseases="" of="" children,="" 131:1032,="" 1977.="" 18.="" forman,="" j.,="" h.="" j.="" baluarte,="" and="" a.="" b.="" gruskin,="" ``hypokalemia="" after="" hypertonic="" phosphate="" enemas,''="" journal="" of="" pediatrics,="" 94:149-="" 151,="" 1979.="" 19.="" martin,="" r.="" r.="" et="" al.,="" ``fatal="" poisoning="" from="" sodium="" phosphate="" enema,="" case="" report="" and="" experimental="" study,''="" journal="" of="" the="" american="" medical="" association,="" 257:2190-2192,="" 1987.="" 20.="" reedy,="" j.="" c.,="" and="" g.="" t.="" zwiren,="" ``enema-induced="" hypocalcemia="" and="" hyperphosphatemia="" leading="" to="" cardiac="" arrest="" during="" induction="" of="" anesthesia="" in="" an="" outpatient="" surgery="" center,''="" anesthesiology,="" 59:578-579,="" 1983.="" 21.="" davis,="" r.="" et="" al.,="" ``hypocalcemia,="" hyperphosphatemia,="" and="" dehydration="" following="" a="" single="" hypertonic="" phosphate="" enema,''="" journal="" of="" pediatrics,="" 90:484-485,="" 1977.="" 22.="" swerdlow,="" d.="" b.,="" s.="" labow,="" and="" f.="" j.="" d'anna,="" ``tetany="" and="" enemas:="" report="" of="" a="" case,''="" diseases="" of="" the="" colon="" and="" the="" rectum,="" 17:786-787,="" 1973.="" 23.="" biberstein,="" m.,="" and="" b.="" a.="" parker,="" enema-induced="" hyperphosphatemia,="" the="" american="" journal="" of="" medicine,="" 79:645-646,="" 1985.="" 24.="" fonkalsrud,="" e.,="" and="" j.="" keen,="" ``hypernatremic="" dehydration="" hypertonic="" enemas="" in="" congenital="" megacolon,''="" the="" journal="" of="" the="" american="" medical="" association,="" 199:574-586,="" 1967.="" 25.="" grosskopf,="" i.="" et="" al.,="" ``hyperphosphatemia="" and="" hypocalcaemia="" induced="" by="" hypertonic="" phosphate="" enema--an="" experimental="" study="" and="" review="" of="" the="" literature,''="" human="" and="" experimental="" toxicology,="" 10:351-355,="" 1991.="" 26.="" rohack,="" j.="" j.,="" b.="" r.="" mehta,="" and="" k.="" subramanyam,="" ``hyperphosphatemia="" and="" hypocalcemic="" coma="" associated="" with="" phosphate="" enema,''="" south="" medical="" journal,="" 78:1241-1242,="" 1985.="" iv.="" summary="" of="" significant="" changes="" from="" the="" proposed="" rule="" the="" agency="" is="" making="" the="" following="" changes="" based="" on="" comments="" submitted="" in="" response="" to="" the="" proposal="" (59="" fr="" 15139)="" and="" other="" relevant="" information="" that="" has="" come="" to="" the="" agency's="" attention.="" the="" agency="" had="" proposed="" to="" include="" the="" package="" size="" limitation="" and="" the="" labeling="" in="" the="" final="" monograph="" for="" otc="" laxative="" drug="" products="" (proposed="" 21="" cfr="" part="" 334).="" however,="" that="" final="" monograph="" has="" not="" been="" completed="" to="" date.="" therefore,="" at="" this="" time="" the="" agency="" is="" including="" this="" information="" in="" part="" 201="" subpart="" g,="" specific="" labeling="" requirements="" for="" specific="" drug="" products.="" new="" sec.="" 201.307="" will="" be="" titled="" sodium="" phosphates;="" package="" size="" limitation,="" warnings,="" and="" directions="" for="" over-the-counter="" sale.="" when="" the="" laxative="" final="" monograph="" is="" complete,="" it="" will="" incorporate="" the="" requirements="" in="" sec.="" 201.307.="" a="" summary="" of="" the="" changes="" made="" by="" the="" agency="" follows:="" 1.="" the="" package="" size="" limitation="" of="" 90="" ml="" (3="" oz)="" for="" sodium="" phosphates="" oral="" solution="" proposed="" in="" sec.="" 334.25="" appears="" in="" sec.="" 201.307(b)(1)="" and="" is="" effective="" 30="" days="" after="" date="" of="" publication="" of="" this="" final="" rule="" in="" the="" federal="" register.="" the="" relabeling="" requirements="" in="" sec.="" 201.307="" are="" effective="" 120="" days="" after="" date="" of="" publication="" of="" this="" final="" rule="" in="" the="" federal="" register.="" (see="" comment="" 2="" in="" section="" ii="" of="" this="" document.)="" 2.="" the="" agency="" has="" revised="" the="" warning="" for="" oral="" and="" rectal="" dosage="" forms="" of="" sodium="" phosphates="" proposed="" in="" sec.="" 334.58(c)(2)(iv).="" the="" agency="" is="" adding="" a="" new="" warning="" for="" oral="" sodium="" phosphates="" products,="" which="" appears="" in="" sec.="" 201.307(b)(2)(i)="" and="" states:="" ``taking="" more="" than="" the="" recommended="" dose="" in="" 24="" hours="" can="" be="" harmful.''="" (see="" comment="" 5="" in="" section="" ii="" of="" this="" document.)="" the="" agency="" is="" adding="" a="" new="" warning="" for="" rectal="" sodium="" phosphates="" products,="" which="" appears="" in="" sec.="" 201.307(b)(2)(ii)="" and="" states:="" ``using="" more="" than="" one="" enema="" in="" 24="" hours="" can="" be="" harmful.''="" these="" warnings="" must="" appear="" in="" boldface="" type="" and="" must="" be="" the="" first="" statement="" in="" product="" labeling="" under="" the="" heading="" ``warnings.''="" [[page="" 27842]]="" 3.="" the="" agency="" is="" adding="" new="" directions="" in="" sec.="" 201.307(b)(3)(i)="" for="" oral="" and="" rectal="" sodium="" phosphates="" that="" state:="" ``do="" not''="" (``take''="" or="" ``use'')="" ``more="" unless="" directed="" by="" a="" doctor.="" see="" warnings.''="" (see="" comment="" 4="" in="" section="" ii="" of="" this="" document.)="" these="" directions="" must="" be="" in="" boldface="" type="" and="" immediately="" precede="" the="" dosage="" information.="" 4.="" the="" agency="" is="" including="" specific="" directions="" in="" sec.="" 201.307(b)(3)(ii)="" that="" inform="" consumers="" not="" to="" take="" more="" than="" the="" recommended="" daily="" dose="" in="" a="" 24-hour="" period.="" (see="" comment="" 3="" in="" section="" ii="" of="" this="" document.)="" v.="" the="" agency's="" final="" conclusions="" on="" otc="" laxative="" drug="" products="" containing="" sodium="" phosphates="" the="" agency="" has="" determined="" that="" there="" is="" sufficient="" evidence="" to="" show="" that="" an="" overdose="" of="" sodium="" phosphates="" products="" can="" cause="" an="" electrolyte="" imbalance.="" this="" imbalance="" can="" occur="" if="" an="" excess="" dose="" of="" either="" the="" sodium="" phosphates="" oral="" solution="" or="" the="" sodium="" phosphates="" enema="" were="" used.="" this="" electrolyte="" imbalance="" can="" cause="" severe="" reactions="" and="" result="" in="" death.="" accordingly,="" this="" final="" rule="" establishes="" a="" container="" size="" limit="" for="" oral="" sodium="" phosphates="" products="" and="" new="" warning="" and="" direction="" statements="" for="" otc="" laxative="" drug="" product="" containing="" sodium="" phosphates.="" to="" better="" protect="" consumers="" who="" use="" products="" containing="" these="" ingredients,="" the="" agency="" concludes="" that="" the="" container="" size="" must="" be="" limited="" to="" 90="" ml="" (3="" oz).="" in="" addition,="" labeling="" needs="" to="" alert="" consumers="" not="" to="" exceed="" the="" recommended="" dose="" of="" an="" oral="" or="" rectal="" sodium="" phosphates="" product="" in="" a="" 24-hour="" period.="" therefore,="" the="" agency="" is="" requiring="" the="" following="" warning="" for="" oral="" dosage="" forms="" of="" sodium="" phosphates="" in="" sec.="" 201.307(b)(2)(i):="" ``taking="" more="" than="" the="" recommended="" dose="" in="" 24="" hours="" can="" be="" harmful.''="" the="" agency="" is="" also="" requiring="" a="" similar="" warning="" for="" rectal="" dosage="" forms="" of="" sodium="" phosphates="" in="" sec.="" 201.307(b)(2)(ii):="" ``using="" more="" than="" one="" enema="" in="" 24="" hours="" can="" be="" harmful.''="" furthermore,="" the="" agency="" is="" requiring="" that="" the="" directions="" for="" oral="" and="" rectal="" sodium="" phosphates="" products="" in="" sec.="" 201.307(b)(3)(i)="" state:="" ``do="" not''="" (``take''="" or="" ``use'')="" ``more="" unless="" directed="" by="" a="" doctor.="" see="" warnings.''="" these="" additional="" statements="" are="" intended="" to="" refer="" consumers="" to="" the="" warnings="" when="" they="" read="" the="" directions="" for="" the="" product.="" because="" of="" the="" dire="" consequences="" that="" can="" occur="" from="" an="" overdose="" of="" sodium="" phosphates,="" the="" warnings="" are="" required="" to="" appear="" in="" boldface="" type="" as="" the="" first="" sentence="" under="" the="" heading="" ``warnings.''="" the="" direction="" statements="" are="" required="" to="" appear="" in="" boldface="" type="" immediately="" preceding="" the="" dosage="" information.="" in="" addition,="" the="" agency="" is="" including="" specific="" directions="" that="" inform="" consumers="" not="" to="" take="" more="" than="" the="" recommended="" daily="" dose="" in="" a="" 24-hour="" period="" in="" sec.="" 201.307(b)(3)(ii).="" (see="" comment="" 3="" in="" section="" ii="" of="" this="" document.)="" vi.="" analysis="" of="" impacts="" no="" comments="" were="" received="" in="" response="" to="" the="" agency's="" request="" for="" specific="" comment="" on="" the="" economic="" impact="" of="" this="" rulemaking="" (59="" fr="" 15139="" at="" 15141).="" fda="" has="" examined="" the="" impacts="" of="" the="" final="" rule="" under="" executive="" order="" 12866="" and="" the="" regulatory="" flexibility="" act="" (5="" u.s.c.="" 601-="" 612).="" executive="" order="" 12866="" directs="" agencies="" to="" assess="" all="" costs="" and="" benefits="" of="" available="" regulatory="" alternatives="" and,="" when="" regulation="" is="" necessary,="" to="" select="" regulatory="" approaches="" that="" maximize="" net="" benefits="" (including="" potential="" economic,="" environmental,="" public="" health="" and="" safety,="" and="" other="" advantages;="" distributive="" impacts;="" and="" equity).="" under="" the="" regulatory="" flexibility="" act,="" if="" a="" rule="" has="" a="" significant="" economic="" impact="" on="" a="" substantial="" number="" of="" small="" entities,="" an="" agency="" must="" analyze="" regulatory="" options="" that="" minimize="" any="" significant="" impact="" of="" the="" rule="" on="" small="" entities.="" title="" ii="" of="" the="" unfunded="" mandates="" reform="" act="" (2="" u.s.c.="" 1501="" et="" seq.)="" requires="" that="" agencies="" prepare="" a="" written="" statement="" and="" economic="" analysis="" before="" proposing="" any="" rule="" that="" may="" result="" in="" an="" expenditure="" in="" any="" one="" year="" by="" state,="" local,="" and="" tribal="" governments,="" in="" the="" aggregate,="" or="" by="" the="" private="" sector,="" of="" $100="" million="" (adjusted="" annually="" for="" inflation).="" the="" proposed="" rule="" that="" has="" led="" to="" the="" development="" of="" this="" final="" rule="" was="" published="" on="" march="" 31,="" 1994,="" before="" the="" unfunded="" mandates="" reform="" act="" was="" enacted.="" the="" agency="" explains="" in="" this="" final="" rule="" that="" the="" final="" rule="" will="" not="" result="" in="" an="" expenditure="" in="" any="" 1="" year="" by="" state,="" local,="" and="" tribal="" governments,="" in="" the="" aggregate,="" or="" by="" the="" private="" sector,="" of="" $100="" million.="" the="" agency="" believes="" that="" this="" final="" rule="" is="" consistent="" with="" the="" principles="" set="" out="" in="" the="" executive="" order="" and="" in="" these="" two="" statutes.="" the="" purpose="" of="" this="" final="" rule="" is="" to="" limit="" the="" otc="" container="" size="" of="" one="" laxative="" drug="" product="" (sodium="" phosphates="" oral="" solution)="" to="" not="" more="" than="" 90="" ml="" and="" to="" add="" warning="" and="" direction="" statements="" to="" the="" labeling="" of="" oral="" and="" rectal="" otc="" sodium="" phosphates="" drug="" products.="" this="" container="" size="" limitation="" and="" the="" warning="" and="" direction="" statements="" concern="" product="" toxicity="" and="" are="" intended="" to="" help="" ensure="" the="" safe="" and="" effective="" use="" of="" all="" otc="" sodium="" phosphates="" drug="" products.="" potential="" benefits="" include="" reduced="" toxicity="" when="" consumers="" use="" these="" products.="" the="" manufacturer="" of="" the="" only="" major="" trade="" product="" containing="" sodium="" phosphates="" oral="" solution="" marketed="" in="" a="" container="" size="" larger="" that="" 90="" ml="" has="" already="" withdrawn="" that="" size="" product="" from="" the="" market.="" the="" agency="" is="" not="" able="" to="" identify="" any="" other="" sodium="" phosphates="" oral="" solution="" marketed="" by="" another="" manufacturer="" in="" a="" container="" exceeding="" 90="" ml.="" regarding="" relabeling,="" the="" agency="" has="" been="" informed="" that="" relabeling="" costs="" of="" the="" type="" required="" by="" this="" final="" rule="" generally="" average="" about="" $2,000="" to="" $3,000="" per="" stock="" keeping="" unit="" (sku)="" (individual="" products,="" packages,="" and="" sizes).="" the="" agency="" is="" aware="" of="" 3="" manufacturers="" that="" together="" produce="" 4="" sku's="" of="" oral="" sodium="" phosphates="" drug="" products="" and="" approximately="" 125="" sku's="" of="" rectal="" sodium="" phosphates="" drug="" products.="" there="" may="" be="" a="" few="" additional="" small="" manufacturers="" or="" a="" few="" additional="" products="" in="" the="" marketplace="" that="" are="" not="" identified="" in="" the="" sources="" fda="" reviewed.="" assuming="" that="" there="" are="" about="" 130="" affected="" otc="" sku's="" in="" the="" marketplace,="" total="" one-time="" costs="" of="" relabeling="" would="" be="" $260,000="" to="" $390,000.="" the="" agency="" believes="" that="" actual="" cost="" could="" be="" lower="" for="" several="" reasons.="" first,="" most="" of="" the="" label="" changes="" will="" be="" made="" by="" private="" label="" manufacturers="" that="" tend="" to="" use="" simpler="" and="" less="" expensive="" labeling.="" second,="" the="" agency="" is="" allowing="" supplementary="" labeling="" (e.g.,="" stick-on="" labeling)="" to="" be="" used="" for="" those="" products="" not="" undergoing="" a="" new="" labeling="" printing="" within="" 120="" days.="" the="" final="" rule="" would="" not="" require="" any="" new="" reporting="" and="" recordkeeping="" activities.="" therefore,="" no="" additional="" professional="" skills="" are="" needed.="" there="" are="" no="" other="" federal="" rules="" that="" duplicate,="" overlap,="" or="" conflict="" with="" the="" final="" rule.="" the="" agency="" considered="" but="" rejected="" several="" container="" size="" and="" labeling="" alternatives:="" (1)="" a="" container="" size="" limit="" of="" 45,="" 60,="" or="" 120="" ml;="" (2)="" voluntary="" relabeling;="" (3)="" publication="" of="" the="" labeling="" information="" in="" the="" fda="" drug="" bulletin="" or="" professional="" journals;="" and="" (4)="" an="" exemption="" from="" coverage="" for="" small="" entities.="" the="" alternate="" container="" sizes="" were="" not="" selected="" because="" 90="" ml="" represents="" the="" upper="" limit="" of="" the="" two="" doses="" per="" container="" and="" physicians="" often="" prescribe="" this="" amount="" for="" bowel="" cleansing="" prior="" to="" surgery="" and="" diagnostic="" procedures="" of="" the="" colon.="" the="" agency="" does="" not="" consider="" voluntary="" relabeling="" or="" an="" exemption="" from="" coverage="" acceptable="" because="" they="" do="" not="" assure="" that="" consumers="" or="" health="" professionals="" will="" have="" the="" most="" recent="" needed="" information="" for="" safe="" and="" effective="" use="" of="" these="" sodium="" [[page="" 27843]]="" phosphates="" drug="" products.="" the="" agency="" considers="" the="" third="" alternative="" useful="" and="" may="" proceed="" with="" such="" publications.="" however,="" such="" publications="" do="" not="" provide="" a="" permanent="" labeling="" requirement,="" which="" the="" agency="" considers="" necessary="" for="" these="" products.="" this="" final="" rule="" may="" have="" a="" significant="" economic="" impact="" on="" the="" manufacturers="" of="" this="" product,="" all="" of="" which="" are="" considered="" small="" entities,="" using="" the="" u.s.="" small="" business="" administration="" designations="" for="" this="" industry="" (750="" employees).="" the="" agency="" believes="" that="" any="" other="" unidentified="" manufacturer="" of="" these="" products="" may="" also="" be="" a="" small="" entity.="" these="" manufacturers="" will="" need="" to="" change="" the="" information="" panel="" of="" each="" affected="" sodium="" phosphates="" sku.="" among="" the="" steps="" the="" agency="" is="" taking="" to="" minimize="" the="" impact="" on="" these="" small="" entities="" are:="" (1)="" to="" provide="" 120="" days="" for="" implementation,="" as="" one="" comment="" requested,="" to="" enable="" entities="" to="" use="" up="" some="" existing="" labeling="" stock,="" and="" (2)="" to="" provide="" for="" the="" use="" of="" supplementary="" labeling="" (e.g.,="" stick-on="" labeling)="" if="" necessary.="" the="" agency="" believes="" that="" these="" actions="" should="" help="" reduce="" the="" relabeling="" cost="" for="" small="" entities.="" the="" agency="" considered="" a="" longer="" implementation="" period.="" the="" agency="" proposed="" a="" 30-day="" effective="" date,="" considered="" extending="" this="" to="" 60="" days,="" and="" in="" response="" to="" public="" comment="" has="" extended="" the="" effective="" date="" to="" 120="" days="" to="" reduce="" the="" economic="" burden="" on="" small="" entities.="" the="" agency="" considered="" but="" rejected="" a="" longer="" effective="" date="" because="" it="" would="" not="" assure="" that="" consumers="" have="" the="" most="" recent="" needed="" information="" for="" safe="" and="" effective="" use="" of="" otc="" sodium="" phosphates="" drug="" products="" at="" the="" earliest="" possible="" time.="" the="" agency="" concludes="" that="" the="" overriding="" safety="" considerations="" warrant="" a="" 120-day="" implementation="" period.="" the="" analysis="" shows="" that="" this="" final="" rule="" is="" not="" economically="" significant="" under="" executive="" order="" 12866="" and="" that="" the="" agency="" has="" undertaken="" important="" steps="" to="" reduce="" the="" burden="" to="" small="" entities.="" nevertheless,="" some="" entities,="" especially="" those="" private="" label="" manufacturers="" that="" provide="" labeling="" for="" a="" number="" of="" the="" affected="" products,="" may="" incur="" significant="" impacts.="" thus,="" this="" economic="" analysis,="" together="" with="" other="" relevant="" sections="" of="" this="" document,="" serves="" as="" the="" agency's="" final="" regulatory="" flexibility="" analysis,="" as="" required="" under="" the="" regulatory="" flexibility="" act.="" finally,="" this="" analysis="" shows="" that="" the="" unfunded="" mandates="" act="" does="" not="" apply="" to="" the="" final="" rule="" because="" it="" would="" not="" result="" in="" an="" expenditure="" in="" any="" one="" year="" by="" state,="" local,="" and="" tribal="" governments,="" in="" the="" aggregate,="" or="" by="" the="" private="" sector,="" of="" $100="" million.="" vii.="" paperwork="" reduction="" act="" of="" 1995="" fda="" concludes="" that="" the="" labeling="" requirements="" in="" this="" document="" are="" not="" subject="" to="" review="" by="" the="" office="" of="" management="" and="" budget="" because="" they="" do="" not="" constitute="" a="" ``collection="" of="" information''="" under="" the="" paperwork="" reduction="" act="" of="" 1995="" (44="" u.s.c.="" 3501="" et="" seq.).="" rather,="" the="" labeling="" statements="" are="" a="" ``public="" disclosure="" of="" information="" orginally="" supplied="" by="" the="" federal="" government="" to="" the="" recipient="" for="" the="" purpose="" of="" disclosure="" to="" the="" public''="" (5="" cfr="" 1320.3(c)(2)).="" viii.="" environmental="" impact="" the="" agency="" has="" determined="" under="" 21="" cfr="" 25.31(c)="" that="" this="" action="" is="" of="" a="" type="" that="" does="" not="" individually="" or="" cumulatively="" have="" a="" significant="" effect="" on="" the="" human="" environment.="" therefore,="" neither="" an="" environmental="" assessment="" nor="" an="" environmental="" impact="" statement="" is="" required.="" list="" of="" subjects="" in="" 21="" cfr="" part="" 201="" drugs,="" labeling,="" reporting="" and="" recordkeeping="" requirements.="" therefore,="" under="" the="" federal="" food,="" drug,="" and="" cosmetic="" act,="" and="" under="" authority="" delegated="" to="" the="" commissioner="" of="" food="" and="" drugs,="" 21="" cfr="" part="" 201="" is="" amended="" as="" follows:="" part="" 201--labeling="" 1.="" the="" authority="" citation="" for="" 21="" cfr="" part="" 201="" continues="" to="" read="" as="" follows:="" authority:="" 21="" u.s.c.="" 321,="" 331,="" 351,="" 352,="" 353,="" 355,="" 356,="" 357,="" 358,="" 360,="" 360b,="" 360gg-360ss,="" 371,="" 374,="" 379e;="" 42="" u.s.c.="" 216,="" 241,="" 262,="" 264.="" 2.="" section="" 201.307="" is="" added="" to="" subpart="" g="" to="" read="" as="" follows:="" sec.="" 201.307="" sodium="" phosphates;="" package="" size="" limitation,="" warnings,="" and="" directions="" for="" over-the-counter="" sale.="" (a)="" reports="" in="" the="" medical="" literature="" and="" data="" accumulated="" by="" the="" food="" and="" drug="" administration="" indicate="" that="" multiple="" container="" sizes="" of="" sodium="" phosphates="" oral="" solution="" available="" in="" the="" marketplace="" have="" caused="" consumer="" confusion="" and="" appear="" to="" have="" been="" involved="" in="" several="" consumer="" deaths.="" sodium="" phosphates="" oral="" solution="" has="" been="" marketed="" in="" 45-milliliter="" (ml),="" 90-ml,="" and="" 240-ml="" container="" sizes.="" the="" 45-ml="" and="" 90-ml="" container="" sizes="" of="" sodium="" phosphates="" oral="" solution="" are="" often="" recommended="" and="" prescribed="" by="" physicians="" for="" bowel="" cleansing="" prior="" to="" surgery="" and="" diagnostic="" procedures="" of="" the="" colon.="" sodium="" phosphates="" oral="" solution="" (adult="" dose="" 20="" ml="" to="" 45="" ml)="" is="" also="" used="" as="" an="" over-the-="" counter="" (otc)="" laxative="" for="" the="" relief="" of="" occasional="" constipation.="" accidental="" overdosing="" and="" deaths="" have="" occurred="" because="" the="" 240-ml="" container="" was="" mistakenly="" used="" instead="" of="" the="" 45-ml="" or="" 90-ml="" container.="" the="" food="" and="" drug="" administration="" is="" limiting="" the="" amount="" of="" sodium="" phosphates="" oral="" solution="" to="" not="" more="" than="" 90="" ml="" (3="" ounces="" (oz))="" per="" otc="" container="" because="" of="" the="" serious="" health="" risks="" associated="" with="" the="" ingestion="" of="" larger="" than="" intended="" doses="" of="" this="" product.="" further,="" because="" an="" overdose="" of="" either="" oral="" or="" rectal="" enema="" sodium="" phosphates="" can="" cause="" an="" electrolyte="" imbalance,="" additional="" warning="" and="" direction="" statements="" are="" required="" for="" the="" safe="" use="" of="" any="" otc="" laxative="" drug="" product="" containing="" sodium="" phosphates.="" (b)="" any="" otc="" drug="" product="" for="" laxative="" or="" bowel="" cleansing="" use="" containing="" sodium="" phosphates="" as="" an="" active="" ingredient="" when="" marketed="" as="" described="" in="" paragraph="" (a)="" of="" this="" section="" is="" misbranded="" within="" the="" meaning="" of="" section="" 502="" of="" the="" federal="" food,="" drug,="" and="" cosmetic="" act="" unless="" packaged="" and="" labeled="" as="" follows:="" (1)="" package="" size="" limitation="" for="" sodium="" phosphates="" oral="" solution:="" container="" shall="" not="" contain="" more="" than="" 90="" ml="" (3="" oz).="" (2)="" warnings.="" the="" following="" sentences="" shall="" appear="" in="" boldface="" type="" as="" the="" first="" statement="" under="" the="" heading="" ``warnings.''="" (i)="" oral="" dosage="" forms.="" ``taking="" more="" than="" the="" recommended="" dose="" in="" 24="" hours="" can="" be="" harmful.''="" (ii)="" rectal="" enema="" dosage="" forms.="" ``using="" more="" than="" one="" enema="" in="" 24="" hours="" can="" be="" harmful.''="" (3)="" directions--(i)="" the="" labeling="" of="" all="" orally="" or="" rectally="" administered="" otc="" drug="" products="" containing="" sodium="" phosphates="" shall="" contain="" the="" following="" directions="" in="" boldface="" type="" immediately="" preceding="" the="" dosage="" information:="" ``do="" not''="" (``take''="" or="" ``use'')="" ``more="" unless="" directed="" by="" a="" doctor.="" see="" warnings.''="" (ii)="" for="" products="" containing="" dibasic="" sodium="" phosphate/monobasic="" sodium="" phosphate="" identified="" in="" sec.="" 334.16(d)="" marketed="" as="" a="" solution.="" adults="" and="" children="" 12="" years="" of="" age="" and="" over:="" oral="" dosage="" is="" dibasic="" sodium="" phosphate="" 3.42="" to="" 7.56="" grams="" (g)="" and="" monobasic="" sodium="" phosphate="" 9.1="" to="" 20.2="" g="" (20="" to="" 45="" ml="" dibasic="" sodium="" phosphate/monobasic="" sodium="" phosphate="" oral="" solution)="" as="" a="" single="" daily="" dose.="" ``do="" not="" take="" more="" than="" 45="" ml="" (9="" teaspoonfuls="" or="" 3="" tablespoonfuls)="" in="" a="" 24-hour="" period.''="" children="" 10="" and="" 11="" years="" of="" age:="" oral="" dosage="" is="" dibasic="" sodium="" phosphate="" 1.71="" to="" 3.78="" g="" and="" monobasic="" sodium="" phosphate="" 4.5="" to="" 10.1="" g="" (10="" to="" 20="" ml="" dibasic="" sodium="" phosphate/monobasic="" sodium="" phosphate="" oral="" solution)="" as="" a="" single="" daily="" dose.="" ``do="" not="" take="" more="" than="" 20="" ml="" (4="" teaspoonfuls)="" in="" a="" 24-="" [[page="" 27844]]="" hour="" period.''="" children="" 5="" to="" 9="" years="" of="" age:="" oral="" dosage="" is="" dibasic="" sodium="" phosphate="" 0.86="" to="" 1.89="" g="" and="" monobasic="" sodium="" phosphate="" 2.2="" to="" 5.05="" g="" (5="" to="" 10="" ml="" dibasic="" sodium="" phosphate/monobasic="" sodium="" phosphate="" oral="" solution)="" as="" a="" single="" daily="" dose.="" ``do="" not="" take="" more="" than="" 10="" ml="" (2="" teaspoonfuls)="" in="" a="" 24-hour="" period.''="" children="" under="" 5="" years="" of="" age:="" ask="" a="" doctor.="" (c)="" after="" june="" 22,="" 1998,="" for="" package="" size="" limitation="" and="" september="" 18,="" 1998,="" for="" labeling="" in="" accord="" with="" paragraph="" (b)="" of="" this="" section,="" any="" such="" otc="" drug="" product="" initially="" introduced="" or="" initially="" delivered="" for="" introduction="" into="" interstate="" commerce,="" or="" any="" such="" drug="" product="" that="" is="" repackaged="" or="" relabeled="" after="" these="" dates="" regardless="" of="" the="" date="" the="" product="" was="" manufactured,="" initially="" introduced,="" or="" initially="" delivered="" for="" introduction="" into="" interstate="" commerce,="" that="" is="" not="" in="" compliance="" with="" this="" section="" is="" subject="" to="" regulatory="" action.="" dated:="" april="" 28,="" 1998.="" william="" k.="" hubbard,="" associate="" commissioner="" for="" policy="" coordination.="" [fr="" doc.="" 98-12053="" filed="" 5-20-98;="" 8:45="" am]="" billing="" code="" 4160-01-f="">