Document ID: FDA-1978-N-0021-0037
Agency: fda
Document Type: Proposed Rule
Title: Notice of Proposed Rulemaking re Professional Labeling for Laxative Drug Products for Over-the-Counter Human Use: Amendment to Tentative Final Monograph
Posted Date: 2011-02-11T05:00Z

[Federal Register Volume 76, Number 29 (Friday, February 11, 2011)]
[Proposed Rules]
[Pages 7743-7757]
From the Federal Register Online via the Government Printing Office [www.gpo.gov]
[FR Doc No: 2011-3091]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 310 and 334

[Docket No. FDA-1978-N-0021; Formerly Docket No. 78N-036L]
RIN 0910-AF38

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

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing a proposed 
rulemaking to amend the tentative final monograph (1985 TFM) for over-
the-counter (OTC) laxative drug products (products that relieve 
occasional constipation). FDA is proposing that sodium phosphate salts 
(dibasic sodium phosphate, monobasic sodium phosphate, and the 
combination of dibasic sodium phosphate/monobasic sodium phosphate 
salts in a solution dosage form) are not generally recognized as safe 
(GRAS) for bowel cleansing. This document also would withdraw the 
professional labeling proposed for sodium phosphate salts in the 1985 
TFM. Professional labeling is additional information about an OTC drug 
that is directed to healthcare professionals who prescribe, administer, 
or dispense medications and is not included in OTC drug product 
labeling for consumers. FDA is issuing this proposed rule after a 
careful review of new data and information on the serious side effects 
that have been associated with the customary dose of OTC sodium 
phosphates solution (approximately 60 grams (g) of sodium phosphates 
taken in two 45-milliliter (mL) doses 12 hours apart or approximately 
50 g of sodium phosphates taken in a 45-mL dose followed by a 30-mL 
dose 12 hours later) for bowel cleansing prior to colonoscopy. This 
proposed rule is part of FDA's ongoing review of OTC drug products.

DATES: Submit electronic or written comments by March 14, 2011. See 
section VI of this document for the effective date of any final rule 
that may publish based on this proposal.

ADDRESSES: You may submit comments, identified by Docket No. FDA-1978-
N-0021 (formerly Docket No. 78-N-036L) and RIN number 0910-AF38, by any 
of the following methods:

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.

Written Submissions

    Submit written submissions in the following ways:
     FAX: 301-827-6870.
     Mail/Hand delivery/Courier (For paper, disk, or CD-ROM 
submissions): Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
    Instructions: All submissions received must include the agency 
name, docket number (Docket No. FDA-1978-N-0021) (formerly Docket No. 
78N-036L) and Regulatory Information Number (RIN) (RIN 0910-AF38) for 
this rulemaking. All comments received may be posted without change to 
http://www.regulations.gov including any personal information provided. 
For additional information on submitting comments, see the ``Comments'' 
heading of the SUPPLEMENTARY INFORMATION section of this document.
    Docket: For access to the docket, to read background documents or 
comments received, go to http://www.regulations.gov and insert the 
docket number, found in brackets in the heading of this document, into 
the ``Search'' box and follow the prompts

[[Page 7744]]

and/or go to the Division of Dockets Management, 5630 Fishers Lane, Rm. 
1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Mary S. Robinson, Center for Drug 
Evaluation and Research, Food and Drug Administration, 10903 New 
Hampshire Ave., Bldg. 22, MS5411, Silver Spring, MD 20993-0002, 301-
796-2090.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Glossary
II. Background
    A. Purpose of the Rule
    B. Chronology of the Federal Register Publications Addressing 
Professional Labeling for Sodium Phosphate Salts in the OTC Laxative 
Drug Products Rulemaking
    C. Other Regulatory History Relevant to This Rulemaking
III. Safety Concerns About the Use of Oral Sodium Phosphate Products 
for Bowel Cleansing
    A. Summary of FDA's Adverse Event Reporting System Data
    B. Summary of the Available Published Data
    C. Consensus Statement on Bowel Preparation Before Colonoscopy
    D. FDA's Tentative Conclusions on the Safety of Nonprescription 
Sodium Phosphate Oral Solutions for Bowel Cleansing
IV. FDA's Tentative Conclusions on the Safety and Effectiveness of 
Other Doses of Sodium Phosphates Oral Solution for Bowel Cleansing
V. Summary of Significant Changes From the 1985 Proposed Rule for 
OTC Laxative Drug Products
VI. Proposed Effective Date
VII. Analysis of Impacts
    A. Background
    B. Need for the Proposed Rule
    C. Impact of the Proposed Rule
    D. Benefits of the Proposed Rule
    E. Alternatives
    F. Impact on Small Businesses
VIII. Paperwork Reduction Act of 1995
IX. Environmental Impact
X. Federalism
XI. References

I. Glossary

    As used in this document:
    ACE inhibitor means angiotension-converting enzyme inhibitor; a 
prescription drug for hypertension.
    Acute phosphate nephropathy means a type of nephrocalcinosis 
attributed to the use of oral sodium phosphate products.
    Acute kidney failure means sudden inability of the kidney to remove 
wastes, concentrate urine, and conserve electrolytes.
    ARB is an abbreviation for angiotension receptor blocker, a 
prescription drug for hypertension.
    Biologic plausibility means a causal association (or relationship 
between two factors) that is consistent with existing medical 
knowledge.
    Bowel cleansing means clearing the lower digestive tract in 
preparation for a colonoscopy.
    Bowel cleansing system means a laxative product containing a 
combination of several different laxative ingredients for sequential 
administration at specified intervals for use in cleansing the bowel 
prior to surgery, colon x-ray, or endoscopic examination.
    Electrolyte disturbance means abnormal levels of electrolytes such 
as sodium, potassium, calcium, or phosphorous found in the blood and 
other body fluids.
    End stage kidney disease means complete or near complete failure of 
the kidneys to function.
    GFR is an abbreviation for glomerular filtration rate; is a measure 
of kidney function. GFR can be obtained by measuring creatinine 
clearance or by estimating creatinine clearance. The creatinine 
clearance is measured by using the values of urine creatinine 
concentration, urine flow rate, and plasma creatinine concentration, 
while the estimated creatinine clearance is calculated by using a 
formula that uses measured serum creatinine. Creatinine clearance is 
not a precise GFR measurement, but rather an accepted surrogate for 
GFR.
    Nephrocalcinosis means a condition characterized by precipitation 
of calcium phosphate in the tubules of the kidney resulting in kidney 
injury.
    NSAID is an abbreviation for nonsteroidal anti-inflammatory drug; 
OTC and prescription drugs that relieve pain and inflammation.
    OSP is an abbreviation for oral sodium phosphates, the combination 
of dibasic sodium phosphate and monobasic sodium phosphate salts in a 
tablet or solution dosage form.
    PEG is an abbreviation for polyethylene glycol, a prescription drug 
used for bowel cleansing.

II. Background

A. Purpose of the Rule

    Oral sodium phosphates (OSP) products are frequently recommended by 
physicians for bowel cleansing prior to a colonoscopy and other medical 
procedures. Both prescription tablet dosage forms and OTC OSP solution 
have been used for this purpose. This document addresses the use of OTC 
OSP solutions for bowel cleansing. The customary dose of OTC OSP 
solution used in medical practice for bowel cleansing is approximately 
60 g of sodium phosphates (dibasic sodium phosphate and monobasic 
sodium phosphate salts) solution taken orally as two 45-mL doses 12 
hours apart or approximately 50 g of sodium phosphates taken as a 45-mL 
dose followed by a 30-mL dose 12 hours later. In the tentative final 
monograph for OTC laxative drug products published January 15, 1985 (50 
FR 2124), FDA proposed labeling for healthcare professionals for the 
use of OTC sodium phosphates solution for bowel cleansing. 
Subsequently, FDA approved sodium phosphates tablets for prescription 
use for bowel cleansing through the new drug application (NDA) approval 
process. However, over the years concerns have been raised about the 
safety of all OSP, both solutions and tablets, for bowel cleansing.
    Most recently, FDA received a petition requesting that FDA either 
withdraw the marketing authorization of OSP for bowel cleansing or 
limit the marketing of these products to prescription only and require 
a ``black box'' warning (Ref. 1). The petition presented the following 
arguments to support these requests:
     Trend data on adverse events demonstrate an increase in 
the number of reports of acute renal failure and nephrocalcinosis 
associated with the use of OSP for bowel cleansing.
     The available published data suggest that the problem is 
larger in scope than initially believed.
     The occurrence of nephrocalcinosis in individuals with no 
identifiable risk factors renders screening insufficient.
     There are equally effective and safer alternative bowel 
preparation agents that are available.

The petition stated that new safety information warrants 
reconsideration of the risk/benefit ratio to the public of the 
continued OTC and prescription use of OSP products for bowel cleansing 
under their present labeling.

    FDA concluded that the currently available information was not 
sufficient to warrant the withdrawal of OSP products from the market. 
However, FDA also concluded that the use of OSP for bowel cleansing 
poses a serious risk of adverse events in some patients and that 
current measures of mitigating these risks have been unsuccessful. 
Therefore, on December 11, 2008, FDA granted the petition's request to 
limit the marketing of OSP products for bowel cleansing to prescription 
only and to require a boxed warning in product labeling (Ref. 2). We 
also concluded that additional measures were necessary to manage the 
potential

[[Page 7745]]

risks associated with the use of prescription OSP products for bowel 
cleansing. Under new authority granted by the Food and Drug 
Administration Amendments Act of 2007, FDA stated that it had notified 
the NDA holder of prescription OSP products that it must develop a risk 
evaluation and mitigation strategy (REMS) that includes the development 
of a Medication Guide and a communication strategy targeted at 
healthcare providers who are likely to prescribe or dispense OSP 
products and/or perform followup assessments of patients following 
bowel cleansing. We also determined that prospective clinical trials 
are necessary to assess the risk of acute kidney injury in patients 
using prescription OSP products for bowel cleansing, and to better 
define the risk factors that predispose patients to such injury.
    Specifically, this document addresses the proposed professional 
labeling for OTC sodium phosphate salts for bowel cleansing described 
in Sec.  334.80 of the 1985 TFM. Under the 1985 TFM, this additional 
labeling would have been provided only to healthcare professionals and 
not the general public, and the labeling would not have been included 
as part of the OTC drug product label. Professional labeling may be 
provided to health professionals in separate labeling distributed by 
pharmaceutical sales representatives. The proposed labeling would have 
provided certain information to healthcare professionals about the use 
of sodium phosphate products for bowel cleansing use. In this document 
we are proposing that the professional labeling for the use of sodium 
phosphates salts for bowel cleansing use be removed from the 1985 TFM 
because of our safety concern with the bowel cleansing use of OSP 
products. This proposed rule does not address the proposed professional 
labeling for bowel cleansing for other active ingredients included in 
Sec.  334.80. FDA intends to address the proposed professional labeling 
of these active ingredients in a future Federal Register publication.
    This proposed rule is consistent with the agency's determination 
that OSP products indicated for bowel cleansing should be limited to 
prescription only. In this document FDA also proposes to classify, the 
individual sodium phosphate salts (i.e., dibasic sodium phosphate and 
monobasic sodium phosphate), as not GRAS (i.e., nonmonograph) for the 
professional labeling indication proposed in the 1985 TFM, i.e., ``For 
use as part of a bowel cleansing regimen in preparing the patient for 
surgery or for preparing the colon for x-ray endoscopic examination.'' 
Thus, this proposed rule would amend Sec.  310.545 (21 CFR 310.545) to 
include sodium phosphate salts, singly and in combination for bowel 
cleansing use as described in Sec.  334.80 of the 1985 TFM.
    In addition, the safety issues raised by the prescription and 
professional use of OSP for bowel cleansing has led FDA to reconsider 
the appropriateness of bowel cleansing, as described in Sec.  334.66, 
as an OTC indication. FDA will address the status of bowel cleansing as 
an OTC indication in a future Federal Register publication.

B. Chronology of the Federal Register Publications Addressing 
Professional Labeling for Sodium Phosphate Salts in the OTC Laxative 
Drug Products Rulemaking

    The current proposal is part of FDA's ongoing review of OTC drug 
products. There are earlier Federal Register publications relevant to 
the use of OTC sodium phosphate salts for bowel cleansing. A summary of 
relevant Federal Register publications is provided in table 1 of this 
document as follows:

   Table 1--OTC Laxative Drug Products Rulemaking for Monobasic Sodium
               Phosphate and Dibasic Sodium Phosphate \1\
------------------------------------------------------------------------
 Federal Register publication           Information in document
------------------------------------------------------------------------
March 21, 1975 (40 FR 12902),  Recommendations of the Advisory Review
 advance notice of proposed     Panel on OTC Laxative, Antidiarrheal,
 rulemaking (ANPR) for OTC      Emetic, and Antiemetic Drug Products
 laxative drug products.        (Panel)
                               Panel recommends:
                                  General recognition of the
                               safety and effectiveness of sodium
                               phosphate salts and the combination of
                               sodium phosphate salts for laxative use.
                                  A professional labeling
                               warning (for healthcare professionals)
                               ``Do not use in patients with megacolon,
                               as hypernatremic dehydration may occur.
                               Use with caution in patients with
                               impaired renal functions as
                               hyperphosphatemia and hypocalcaemia may
                               occur.''
                               The Panel did not recommend that the
                                sodium phosphates salts bear an
                                indication for preparation of the colon
                                for x-ray and endoscopic examination.
                               (50 FR 12902 at 12940 and 12942)
January 15, 1985 (50 FR        FDA adds a provision for OTC bowel
 2124), tentative final         cleansing systems in Sec.   334.32.
 monograph (TFM) for OTC
 laxative drug products.
                               FDA also adds the following professional
                                labeling indication for sodium
                                phosphates oral and rectal solutions,
                                USP: \2\
                                 ``For use as part of a bowel cleansing
                               regimen in preparing the patient for
                               surgery or for preparing the colon for x-
                               ray endoscopic examination.''
                               The proposed professional labeling did
                                not contain directions for the proposed
                                bowel cleansing indication.
                               (50 FR 2124 at 2157)
March 31, 1994 (59 FR 15139)   Based on a number of deaths related to
 Amendment to TFM for OTC       the OTC availability of a 240-milliliter
 laxative drug products.        (mL) container size for sodium
                                phosphates oral solution, FDA proposes
                                an amendment to the 1985 TFM to limit
                                the container size for these products to
                                not greater than 90 mL (3 ounces (oz))
                                and to add a new overdose warning
                                alerting consumers that exceeding the
                                recommended dose can be harmful as
                                follows:
                               ``Do not exceed the recommended dose
                                unless directed by a doctor. Serious
                                side effects may occur from excess
                                dosage.''

[[Page 7746]]

 
May 21, 1998 (63 FR 27836),    FDA determines that the continued OTC
 final rule, package size       availability of a 240-mL container size
 limitation and warning and     of sodium phosphates oral poses a
 directions statements for      serious safety concern and that it
 sodium phosphates oral         cannot wait for a laxative final rule to
 solutions.                     address this concern. FDA publishes a
                                final rule that limits the container
                                sizes to not greater than 90 mL and adds
                                warnings and direction statements for
                                sodium phosphates oral and rectal
                                solutions marketed for laxative and
                                bowel cleansing use that includes the
                                following:
                                  ``Do not (take or use) more
                               unless directed by a doctor.''
                                  ``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 mL dibasic. sodium
                               phosphate/monobasic sodium phosphate oral
                               solution) ``Do not take more than 45 mL
                               (9 teaspoons or 3 tablespoons in a 24-
                               hour period.''
                               FDA also indicates its intention to
                                incorporate the information in 21 CFR
                                201.307 into the final monograph for OTC
                                laxative drug products at a later date.
                               See 21 CFR 201.307. Effective date of the
                                package size limitation portion of the
                                final rule was June 22, 1998, and
                                effective date of the relabeling portion
                                was September 18, 1998.
May 21, 1998 (63 FR 27886),    In an amendment to the 1985 TFM, FDA
 amendment to TFM for OTC       proposes extensive additional labeling
 laxative drug products.        for the professional use of oral and
                                rectal sodium phosphate drug products
                                that:
                                  Warns healthcare professionals
                               about the use of sodium phosphates
                               products in the elderly, in patients
                               taking drugs that may affect electrolyte
                               levels, or in patients with:
                                 [cir] congestive heart failure
                                 [cir] impaired renal function
                                 [cir] heart disease
                                 [cir] acute myocardial infarction
                                 [cir] unstable angina
                                 [cir] preexisting electrolyte
                                  disturbances (such as dehydration, or
                                  those secondary to the use of
                                  diuretics)
                                  Advises monitoring
                               electrolytes and giving sufficient fluid
                               replacement to prevent dehydration.
                                  Describes the adverse effects
                               on electrolyte balance that can occur
                               when one or more doses of sodium
                               phosphates is given in a 24-hour period.
                                  Provides recommendations for
                               the treatment of electrolyte imbalance.
                               FDA also proposes additional warnings
                                about the use of rectal dosage forms of
                                sodium phosphate drug products that:
                                  Warns about the use of rectal
                               dosage forms of sodium phosphate products
                               in children under 2 or in patients with
                                 [cir] megacolon
                                 [cir] imperforate colon
                                 [cir] colostomy
                                 [cir] rectal abnormalities
                                 [cir] and about forcing the enema tip
                                  into the rectum
                               FDA also states that it will not include
                                a dosage greater than 7.56 gm of dibasic
                                sodium phosphate and 20.2 g monobasic
                                sodium phosphate in a 24-hour period in
                                the OTC or professional labeling in the
                                final monograph for OTC laxative drug
                                products.
December 7, 1998 (63 FR        Final rule; stay of compliance with the
 67399).                        relabeling requirements for rectal
                                sodium phosphates in 21 CFR 201.307
                                until September 8, 1998, to allow
                                manufacturer's additional time to
                                relabel their products.
December 9, 1998 (63 FR        FDA withdraws its proposed amendment of
 67817), notice of withdrawal   Sec.   334.80(b)(2) of the 1985 TFM to
 of TFM amendment of May 21,    add expanded professional labeling for
 1998 (63 FR 27886).            oral and rectal sodium phosphates drug
                                products and states the intent to
                                further expand the professional labeling
                                in a future proposed rule.
November 29, 2004 (69 FR       Final rule to extend the sodium content
 69278).                        labeling requirement to sodium
                                phosphates rectal products.
------------------------------------------------------------------------
\1\ In the 1985 TFM (50 FR 2124), FDA referred to dibasic sodium
  phosphate as ``sodium phosphate,'' and monobasic sodium phosphate as
  ``sodium biphosphate.'' This document uses ``dibasic sodium
  phosphate'' and ``monobasic sodium phosphate,'' the official names
  listed in the USP Dictionary of USAN and International Drug Names,
  2008. The document uses the term ``sodium phosphate salts'' to refer
  to dibasic sodium phosphate'' and ``monobasic sodium phosphate''
  separately or in combination.
\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 31/National Formulary 26, 2008. Sodium phosphates rectal
  solution is the official name for a solution of dibasic sodium
  phosphate and monobasic sodium phosphate in the U.S. Pharmacopeia 31/
  National Formulary 26, 2008.

C. Other Regulatory History Relevant to This Rulemaking

1. Citizen Petition To Include Bowel Cleansing Systems Containing 
Sodium Phosphates Oral Solution
    In the 1985 TFM, FDA proposed that certain combination bowel 
cleansing systems could be considered generally recognized as safe and 
effective (GRASE) for OTC use as bowel cleansers (50 FR 2124 at 2153). 
The proposed combinations did not include sodium phosphate ingredients. 
In a petition dated November 12, 1987, and a subsequent supplemental 
submission to the petition, a manufacturer requested that FDA amend the 
1985 TFM to include six bowel cleansing systems (Refs. 3 and 4). In a 
letter dated October 26, 1989, FDA responded to the petition and found 
that two of the six requested kits could be GRASE for OTC use for bowel 
cleansing (Ref. 5). Both kits include sodium phosphates oral solution 
as a component. One kit contains three laxatives for sequential

[[Page 7747]]

administration as follows: sodium phosphates oral solution (7.56 g 
sodium phosphate and 20.2 g sodium biphosphate as a 45-mL solution), 
followed by bisacodyl (20 mg) in an oral dosage form taken at least 3 
hours after the sodium phosphates oral solution, followed by a 
bisacodyl suppository (10 mg) taken at least 9 hours after the oral 
bisacodyl and at least 1 hour before the scheduled procedure. The other 
kit substitutes a bisacodyl enema (10 g) for the bisacodyl suppository. 
In its response, FDA indicated that the Agency intended that both kits 
would be added as GRASE OTC bowel cleansing systems in Sec.  334.32 of 
the final monograph. In a letter dated December 27, 2010, FDA 
subsequently informed the manufacturer of its intention to withdraw its 
proposal to include Sec.  344.66 Bowel Cleansing Systems in the OTC 
laxative final monograph based on concerns about the safety of bowel 
cleansing in the OTC setting (Ref. 6).
2. Citizen Petition To Include in Professional Labeling a Sodium 
Phosphates Oral Solution Two 45-mL Dose Regimen
    In response to the 1985 TFM, one manufacturer filed a petition 
dated March 23, 1993, and supplements to the petition, requesting that 
the professional labeling (Sec.  334.80) be amended to include a bowel 
cleansing regimen consisting of two 45-mL doses of sodium phosphates 
oral solution, administered sequentially 10 to 12 hours apart (Refs. 7 
through 12). A comment on the petition dated September 23, 1993, 
expressed concern about the March 23, 1993, petition request, stating 
that there is a potential for sodium phosphates to induce electrolyte 
and hemodynamic changes when ingested in two sequential doses within 24 
hours (Ref. 13).
    On March 1, 1996, FDA responded to the citizens petition mentioned 
previously, stating that the available data supported the effectiveness 
of the proposed bowel cleansing regimen of two 45-mL doses 10 to 12 
hours apart (Ref. 14). However, FDA emphasized it was concerned about 
the safety of this dosage regimen because of the electrolyte and 
vascular volume changes that could occur. FDA explained that, should 
adequate safety data to support the proposed regimen become available, 
it might be possible for the Agency to consider this dosage regimen of 
two 45-mL doses, administered 10 to 12 hours apart, for inclusion in 
the monograph by professional labeling only. FDA ultimately denied this 
petition (Ref. 7) in a letter dated August 22, 1997, because we 
remained concerned about the safety of that dosing regimen (Ref. 15).
3. Citizen Petition To Limit Sodium Phosphates for Bowel Cleansing to 
Prescription Marketing
    Subsequently, FDA received another citizen petition dated August 
23, 2000, requesting that FDA limit the marketing of sodium phosphates 
oral solution for bowel cleansers to prescription status and to require 
a boxed warning (Ref. 16). On July 19, 2001, FDA denied the petition, 
stating that based on the available data and information; there was 
insufficient evidence at that time to support the petition's request 
(Ref. 17). However, FDA stated that it intended to propose in a future 
issue of the Federal Register to limit the package size of sodium 
phosphates oral solution to 45 mL and to require revised labeling to 
include more information on the safe use of these products by consumers 
and health professionals.
4. Citizen Petition to Include Professional Labeling for Two 30-mL 
Doses to Two 45-mL Doses
    FDA received another citizen petition dated June 25, 2003, 
requesting that the Agency amend the 1985 TFM to include professional 
labeling for two 30-mL to two 45-mL doses of sodium phosphates oral 
solution given sequentially at a 10- to 12-hour dosing interval for 
bowel cleansing prior to diagnostic procedures (Refs. 18 and 19). The 
petition also included recommendations for amending the proposed 
professional labeling (Sec.  334.80).
    FDA also received a number of comments objecting to the petition's 
requested dosing regimen (Refs. 21, 22, and 23). One comment stated 
that the regimen of two doses in 24 hours is not safe, primarily 
because it can cause dangerous electrolyte shifts. The comment asserted 
that the problem is exacerbated because a patient's susceptibility to 
electrolyte changes is not adequately evaluated prior to administration 
for bowel cleansing use, in spite of labeling (Ref. 21). Another 
comment stated that sodium phosphates oral solution should be subject 
to prescription control when used for bowel cleansing (Ref. 22). As an 
alternative to prescription status for sodium phosphates oral solution, 
the comment recommended that FDA limit the bowel cleansing indication 
to situations where sodium phosphates oral solution is included in a 
bowel cleansing system to be administered at a total dose of not more 
than 7.56 g sodium phosphate and 20.2 g sodium monobasic sodium 
phosphate (45 mL). The third comment stated that the sodium phosphate 
bowel cleansing labeling is inadequate to address the continuing 
problems resulting from the electrolyte derangements and volume 
depletion caused by these products (Ref. 23).
    On December 11, 2008, FDA denied this petition (Ref. 20). Based on 
a review of the available data and the lack of data establishing a safe 
dose of OSP for bowel cleansing in the OTC setting, FDA concluded that 
the use of sodium phosphates oral solution for bowel cleansing in the 
OTC setting according to professional labeling in an OTC monograph 
poses an unacceptable risk of serious adverse events. FDA also 
concluded that the use of sodium phosphate oral solution products for 
bowel cleansing meets the statutory standard for prescription products 
set forth in the Federal Food, Drug, and Cosmetic Act (FD&C Act).
5. FDA's Educational Efforts
    FDA has made a number of attempts outside the rulemaking process to 
educate healthcare professionals and consumers about the potential 
risks associated with the use of sodium phosphates oral solution for 
bowel cleansing. In September 17, 2001, a Science Background Paper was 
issued on the ``Safety of Sodium Phosphates Oral Solution'' (Ref. 24), 
in which FDA stated that physicians need to be aware that people at 
increased risk for electrolyte disturbances (e.g., those with 
congestive heart failure, ascites, renal insufficiency, and 
dehydration) may experience serious adverse events if they use a sodium 
phosphates oral solution for bowel cleansing (see section III of this 
document).
    In 2006, FDA issued a health alert and a second Science Background 
Paper stating that a rare but serious form of kidney failure has been 
associated with the use of OSP products for bowel cleansing (Refs. 25 
and 26). In 2008, FDA issued another health alert and provided 
healthcare professionals with updated information on the risks 
associated with the use of OSP for bowel cleansing (Refs. 27 and 28). 
The alert stated that as a result of new safety information, FDA would 
require a Boxed Warning on prescription OSP products as well as the 
development of a REMS for these products (Ref. 27). FDA also stated its 
intention to publish a proposed rule to remove professional labeling 
for OTC OSP for bowel cleansing from the 1985 TFM (50 FR 2124 at 2157). 
FDA posted this information on its Web site at http://www.fda.gov/cder/drug/infopage/osp_solution/default.htm.

[[Page 7748]]

III. Safety Concerns About the Use of Oral Sodium Phosphate Products 
for Bowel Cleansing

A. Summary of FDA's Adverse Event Reporting System Data

    As described previously, FDA has previously made a number of 
attempts to educate healthcare professionals and consumers about the 
risk of adverse effects on the kidneys that have been associated with 
the use of OSP products for bowel cleansing. In addition to measures 
taken by FDA, in 2005 a major manufacturer of OTC sodium phosphates 
oral solution products distributed updated professional labeling 
containing detailed safety information and dosing instructions (60 g of 
sodium phosphates (dibasic sodium phosphate and monobasic sodium 
phosphate salts) solution taken orally as two 45-mL doses 12 hours 
apart or approximately 50 g of sodium phosphates taken as a 45-mL dose 
followed by a 30-mL dose 12 hours later) (Ref. 29). Despite these 
measures and the development of products with a reduced sodium 
phosphate dose, FDA's Adverse Event Reporting System (AERS) continues 
to receive reports of acute kidney injury that have been associated 
with the customary dose of these products for bowel cleansing.
    To date, AERS has received over 100 serious adverse event reports 
associated with the use of prescription and nonprescription OSP 
products for bowel cleansing at the customary dose. Acute renal injury 
associated with this use of OSP for bowel cleansing has led to kidney 
transplant, dialysis, long term renal failure and, in rare instances, 
death. The majority of these cases occurred in patients with additional 
risk factors for kidney injury as identified in the May 2006 Health 
Alert (see section II.C.5 of this document). There were cases, however, 
that occurred in patients without additional risk factors.
    From 1969 to 2005, FDA received 33 reports of acute kidney injury 
reported to be associated with the use of OTC sodium phosphates oral 
solution for bowel cleansing. Among the 33 reports, 4 cases developed 
end-stage kidney disease with one case requiring a kidney transplant. 
At least 22 of the 33 cases developed chronic kidney failure, with at 
least 9 cases requiring hospitalization and 7 requiring dialysis. Only 
5 of the 33 cases of acute kidney injury involved a dose of sodium 
phosphate in excess of 59.4 g.\1\ In addition to the cases of acute 
kidney injury, there were reports of 11 fatalities, 2 cases of seizure, 
and 12 serious cardiac events. Most of the cases with cardiac events 
had electrolyte abnormalities. However, the dose of sodium phosphates 
involved in most of these cases was well in excess of 59.4 g.
---------------------------------------------------------------------------

    \1\ Outcomes are not mutually exclusive.
---------------------------------------------------------------------------

    Since 2005, there have been an additional 46 reports of acute 
kidney failure that have been associated with the use of OTC sodium 
phosphates oral solution for bowel cleansing. Twelve of these cases 
were reported in a published abstract (Ref. 30) with only limited 
information. The remaining 34 cases were reported in the AERS data 
base. Of the AERS cases, one required a kidney transplant, one was 
placed on a kidney transplant list, six required dialysis, and four 
cases had long term decreased kidney function. More recently (January 
2008), FDA received two reports of acute kidney injury associated with 
a lower dose sodium phosphate oral solution regimen, i.e., a 45-mL dose 
followed by 30-mL dose administered 10 to 12 hours apart. Both of these 
cases resulted in hospitalization.
    An OSP in a tablet dosage form has been approved for prescription 
use as a bowel cleanser since 2000. The sodium phosphate dose of this 
product is 60 g. In 2006, FDA approved a sodium phosphate tablet with a 
lower sodium phosphate dose (48 g) for the same indication. There have 
also been a number of reports of acute kidney injury associated with 
the use of both of these products.
    Since 2001, FDA has received 16 cases of acute kidney injury that 
were likely associated with the use of the 60-g prescription product. 
Ten of these cases required hospitalization, and at least two required 
dialysis. Direct evidence of calcium phosphate precipitation in kidney 
tubules was obtained by biopsy in one case. There were also 10 cases of 
seizure. In at least nine of these cases there was no previous history 
of seizure, and seizures began between 2 to 16 hours after use of OSP. 
In all 10 seizure cases, the patient had low blood sodium levels, and 
required hospitalization. Five of the cases of renal failure and two of 
the cases of seizure did not follow labeled directions for use, which 
may have contributed to the adverse event.
    Since approval of the 48-mg dosage form of sodium phosphate tablets 
in 2006, 20 unique cases of kidney injury associated with the use of 
this lower dose product have been reported to AERS through September 
12, 2008. The onset of the kidney injury occurred from several hours to 
21 days after taking the product. Three of these patients had a kidney 
biopsy, the results of which revealed acute phosphate nephropathy. The 
concomitant use of an ACE inhibitor or ARB was noted in 11 cases, 
diuretic use in 6 cases, NSAID use in 4 cases; and 1 patient received a 
contrast dye. Five cases were reported to be life-threatening and 10 
resulted in hospitalization. Of these 20 cases, 4 patients required 
dialysis for an unspecified period of time and 1 patient died from 
complications of pneumonia. Nine patients were reported to have kidney 
impairment that continued for at least 2 to 4 weeks. The status of 
renal impairment is unknown for seven patients.\2\
---------------------------------------------------------------------------

    \2\ Outcomes are not mutually exclusive.
---------------------------------------------------------------------------

B. Summary of the Available Published Data

    In addition to the FDA AERS cases described previously, there are 
also reports of acute kidney injury associated with the use of sodium 
phosphate products for bowel cleansing in the published literature. It 
is not clear from the reports whether these adverse events were 
associated with the use of an OTC or prescription product.
    The 21 cases of acute phosphate nephropathy cited in the May 2006 
Health Alert were identified by Markowitz et al. (Ref. 31) from kidney 
biopsy archives at the Columbia University Renal Pathology Laboratory. 
From 2000 to 2004, the laboratory processed a total of 7,349 native 
renal biopsies (transplanted kidneys were excluded), from which 31 
cases were retrieved with findings of kidney tubule injury and abundant 
calcium deposits. Of these 31 cases, 21 had normal calcium levels and 
met the criteria for acute phosphate nephropathy and had a recent 
colonoscopy preceded by OSP use. The incidence of acute phosphate 
nephropathy reported in this study was 0.29 percent (21 of 7,349).
    Clinical followups were available for all 21 cases (mean 16.7 
months). All 21 cases had increased serum creatinine, an indication of 
decreased kidney function, (mean 3.9 mg/deciliter (mg/dL)) at a median 
of 1 month after colonoscopy. Four cases (19 percent) progressed to end 
stage kidney failure 9 to 18 months (mean 13.8 months) after 
colonoscopy and required dialysis. These four patients required kidney 
replacement therapy, and one of the four underwent successful kidney 
transplant. Although 16 of the remaining 17 cases (94 percent) had a 
subsequent improvement in kidney function, none returned to baseline 
creatinine levels and were left with some degree of renal impairment.
    The demographic and clinical findings for these 21 cases suggest 
that age and the co-administration of agents

[[Page 7749]]

that may reduce kidney circulation are risk factors for the condition. 
Eighteen of the 21 cases were 51 years or older, and 3 were older than 
62. Sixteen of 21 cases (76.2 percent) had a history of hypertension, 
and 14 of the 16 patients with hypertension (87.5 percent) were being 
treated with either an ACE inhibitor or ARB for their hypertension. 
Four cases were taking diuretics and three were on non-steroidal anti-
inflammatory drugs (NSAIDs). Five cases were taking more than one of 
these agents simultaneously. One patient who was 39 years old did not 
have any of the risk factors noted in the series. Also noteworthy, but 
of unclear significance, was that 17 (81 percent) of the 21 cases were 
women.
    Subsequent to the report by Markowitz and the 2006 FDA Health 
Alert, there continued to be reports (Refs. 32 and 33) of acute kidney 
injury associated with the use of OSP. Ma et al. reported cases of 
acute kidney injury in two patients (75-year old male and an 80-year 
old female) who had a history of diabetes mellitus (Ref. 32). Baseline 
serum creatinine was within normal limits, but one patient had 
microalbuminuria (small amounts of protein in the urine), an early 
marker of diabetic kidney disease. Acute kidney injury developed within 
days of receiving OSP bowel prep for colonoscopy. Biopsies were not 
conducted, but the kidney injury was attributed to OSP because of the 
temporal relationship to OSP exposure. The male patient required 5 days 
of dialysis for the acute injury. Both cases resolved, but serum 
creatinine remained elevated above their baseline values. The authors 
noted that patients with diabetes often have decreased renal perfusion 
despite normal serum creatinine and may be at risk for kidney injury 
with OSP.
    Gonlusen et al. reported the case of a 56-year-old woman with 
Crohn's Disease who presented with acute kidney injury approximately 2 
weeks after a colonoscopy (Ref. 33). She received two doses of sodium 
phosphates oral solution (45 ml each dose) prior to the colonoscopy. 
Her baseline creatinine was 0.8 mg/dL. Serum creatinine was 3.5 mg/dL 
at the time of presentation. Kidney biopsy showed calcium phosphate 
deposition in the kidney tubules, that was likely related to the use of 
sodium phosphates oral solution. The acute kidney injury resolved, but 
her serum creatinine remained elevated at 1.6 mg/dL 10 months later.
    The author reviewed the literature and speculated that there are 
two types of acute kidney injury associated with OSP. One type is 
related to the precipitation of calcium phosphate in the kidney 
tubules, such as the case described in this report. The other type 
occurs within several days and is associated with severe electrolyte 
abnormalities and symptoms related to these abnormalities. In the 
literature reviewed by Gonlusen et al., none of the cases had kidney 
biopsies. Some patients had residual elevation of creatinine at 
followup while others had normal creatinine. In some of the reviewed 
cases, abnormalities of blood urea nitrogen or creatinine may have 
reflected severe dehydration.
    Recently published observational, retrospective studies have 
attempted to assess the incidence of subclinical (without symptoms) 
kidney injury after OSP use for bowel preparation (Refs. 34 through 
39). It is not entirely clear how the observations in these studies 
relate to cases of acute phosphate nephropathy that became evident 
because of the development of clinical symptoms that lead physicians to 
conduct testing. These studies only assess changes in serum creatinine 
function in a cohort of people who received OSP for bowel cleansing in 
an attempt to determine whether lesser degrees of kidney injury occur 
in a population receiving OSP. Nevertheless, it is useful to review the 
data in light of our concerns about OSP products for bowel cleansing.
    Hurst et al. found an increased risk of acute kidney injury that 
was associated with OSP use in an observational, retrospective, cohort 
study (Ref. 34). The study included 9,799 subjects over the age of 50 
who had a colonoscopy using either OSP or PEG products and had serum 
creatinine values available within 365 days before and after their 
procedure. Acute kidney injury was defined as greater than or equal to 
a 50-percent increase in serum creatinine over the 12 months following 
colonoscopy.
    A total of 114 patients out of 9,799 developed acute kidney injury. 
Of these, 83 (1.29 percent, 83/6,432) were in the OSP group and 31 
(0.92 percent, 31/3,367) were in the PEG group. On univariate analysis, 
the risk for the developing acute kidney injury was not significantly 
different between the two groups (odds ratio = 1.41; 95 percent 
confidence interval 0.93 to 2.13, p = 0.113). The PEG group, however, 
included high-risk subjects who were significantly older and had a 
higher incidence of diabetes, hypertension, cardiovascular disease, 
chronic kidney disease, and were more likely to be using a diuretic, 
ACE inhibitor, or ARB (all p < 0.05).
    After adjustment for significant covariates and risk factors such 
as age, diabetes, hypertension, acute cardiovascular disease, ACE 
inhibitor or ARB use, and other factors suspected to be associated with 
acute kidney injury, OSP use was found to be associated with an 
increased risk of acute kidney injury (odds ratio = 2.35, 95 percent 
confidence interval 1.51 to 3.66, p < 0.001). Using a more stringent 
definition of acute kidney injury (doubling of serum creatinine), an 
even stronger association between OSP use and acute kidney injury 
emerged (odds ratios = 3.52, 95 percent confidence interval 1.13 to 
10.93, p = 0.03). Followup creatinine values in patients with acute 
kidney injury remained significantly higher, with only 16 percent of 
cases returning to their previous creatinine levels. The changes in 
creatinine levels seen in this study were less severe than those seen 
in the case series compiled by Markowitz et al. (Ref. 31). Hurst et al. 
noted, however, that even small increases in creatinine levels have 
been shown to be associated with increased mortality (Ref. 34).
    Brunelli et al. evaluated 2,237 subjects who underwent colonoscopy 
with a baseline serum creatinine of less than 1.5 mg/dL and compared 
cases that developed acute kidney injury to those who did not in a 
case-controlled study (Ref. 35). Acute kidney injury was defined as 
either a 25-percent or a 0.5-mg/dL increase in serum creatinine from 
baseline (measured within 6 months before the colonoscopy) to 6 months 
after colonoscopy. There were 116 cases of acute kidney injury with 
exposure data that were compared with 349 controls. These authors found 
no association between acute kidney injury and the use of OSP. However, 
a significant interaction (p = 0.03) was found indicating an increased 
risk for kidney injury from OSP products in patients who were 
simultaneously receiving ACE inhibitors or ARBs.
    Abaskharoun et al. (Ref. 36) conducted a retrospective analysis of 
a database of patients who underwent a colonoscopy at their institution 
between 2004 and 2005 in order to detect the occurrence of kidney 
injury in patients who received either OSP or PEG. The study was 
supported by a manufacturer of OSP. The study included only patients 
who had undergone two colonoscopy procedures and had serum creatinine 
measured prior to each procedure. A total of 767 patients were included 
in the study. OSP was used by 618 patients and PEG was used by 149 
patients. The timeframe between the two colonoscopies for the patients 
ranged from 3 months to 9 years.

[[Page 7750]]

    Serum creatinine and estimated creatinine clearance, calculated by 
the Cockroft-Gault equation, were compared between patients receiving 
OSP and PEG. Chronic renal failure was defined as an abnormal 
creatinine or creatinine clearance on the repeat measurement. The 
change in serum creatinine was significantly different (p = 0.005) 
between OSP (-2.0 micromole/liter ([mu]mol/L)) and PEG (0.9 [mu]mol/L), 
suggesting that OSP had less of an effect than PEG, but this difference 
was not felt to be clinically significant by the authors, and there was 
no significant difference in the number of patients with abnormal 
second creatinine values between the two groups. In addition, the 
results were difficult to interpret because:
    1. There is a possibility that selection bias eliminated people who 
developed renal injury from the prep from their first colonoscopy. The 
study only enrolled patients who used the same bowel prep prior to each 
colonoscopy. If a patient received OSP or PEG before their first 
colonoscopy and developed kidney damage as a result, they may not 
receive the same prep again prior to the second colonoscopy. They would 
be excluded from this study because they would have had to receive the 
same prep prior to each procedure. Also, other patients who had only 
one colonoscopy were not included.
    2. There was a wide range of time between measurements of serum 
creatinine. No analysis was provided that looked at potential 
differences related to the time between measurements.
    3. A greater percent of the PEG patients were receiving 
antihypertensive therapy, nonsteroidal anti-inflammatory drugs or had a 
diagnosis of diabetes mellitus, coronary artery disease and 
hypertension. The patients in the PEG group were older than the OSP 
patients. Many of these factors have been reported to be risk factors 
for the development of kidney injury from OSP. Age and use of 
antihypertensives were found in this study to be predictors of renal 
failure.
    4. Chronic renal failure is not adequately defined and may include 
many people who did not have significant kidney injury.
    5. The study is too small to make conclusions about renal function 
decline related to OSP.
    Khurana et al. reported a retrospective study of 286 patients (out 
of more than 3,000 patients) who had undergone colonoscopy or flexible 
sigmoidoscopy between January 1998 and February 2005 and used OSP as 
the bowel prep (Ref. 37). The patients had serum creatinine measured at 
6 months and 12 months after the procedure. Baseline serum creatinine 
had to be less than 1.5 mg/dL and obtained within 6 months prior to 
colonoscopy. Glomerular filtration rate (GFR), a measure of kidney 
function, was calculated using a formula from the Modification in Diet 
in Renal Disease study group (Ref. 38). The formula uses age and serum 
creatinine in the calculation.
    A control group of 125 patients was derived from their database of 
patients who did not have colonoscopy at any time or who had undergone 
colonoscopy prior to 1996 and had post-colonoscopy serum creatinine 
unchanged from prior to colonoscopy. There were no significant 
differences between the two groups regarding demographic and base line 
characteristics as well as the use of concomitant medications. The 
patients were predominately white and female and the mean age was about 
68 years. In the study group, 95 percent had hypertension, 45 percent 
had diabetes, 61 percent were taking an ACE inhibitor and/or ARB and 47 
percent were taking diuretics, which were not significantly different 
as compared to the control group.
    Serum creatinine increased by 0.09 mg/dL in the OSP group and 0.02 
mg/dL in the control group at 6 months (p < .001; 2 sample t test). At 
1 year, the change from baseline was 0.12 mg/dL for OSP and 0.04 mg/dL 
for the controls (p < .001; 2 sample t-test). Because calculated GFR 
used serum creatinine, similar trends were seen when GFR values were 
compared between groups. The authors concluded that OSP is associated 
with a decline in GFR in elderly patients with normal creatinine.
    It is difficult to make definitive conclusions from this study for 
the following reasons:
    1. Less than one-tenth of the patients who had a colonoscopy were 
included in the study. The study size is small and sampling may not be 
random.
    2. The control group included patients who had the same creatinine 
after a previous colonoscopy. This could introduce a selection bias 
because it picked people with stable renal function. The number of 
these patients in the control group, which included patients without 
colonoscopy, is not provided.
    3. The majority of subjects had conditions that may predispose them 
to kidney injury (e.g. hypertension) or were receiving drugs that may 
make them susceptible to toxicity with OSP. It is also unclear how 
these findings can be extrapolated to people without risk factors for 
kidney injury.
    4. Serum creatinine and calculated GFR are not adequate surrogates 
to detect small changes in glomerular filtration rate as a function of 
time.
    5. It would have been helpful to describe the number of patients 
who exceeded some percent increase in creatinine or some absolute 
value. The upper range of creatinine is greater than 3.0 mg/dL at 1 
year in both groups.
    This study, however, raises important issues that need to be 
addressed. Patients will undergo multiple colonoscopies over the years, 
and it is important to understand whether exposure to OSP can lead to 
small amounts of kidney damage that may be cumulative after repeated 
exposure.
    A retrospective study by Russman et al. compared the risk of kidney 
impairment in patients who used OSP or PEG prior to colonoscopy based 
on clinical and electronic records from the Henry Ford Health System 
(HFHS) in Detroit, MI (Ref. 39). The base study population (7,897 
patients) consisted of patients who had a colonoscopy at the HFHS 
Detroit Center gastroenterology clinic between November 1999 and 
October 2005. Patients were included if they had a creatinine 
determination 12 months prior to and 6 months after colonoscopy and a 
GFR greater than or equal to 60 (milliliter per minute (mL/min). 
Patients with preexisting kidney disease within 12 months of 
colonoscopy were excluded from further evaluation based on prespecified 
criteria (e.g., undergoing dialysis, history of kidney transplant, 
acute as well as chronic renal failure, or GFR < 60 mL/min). Impaired 
renal function after colonoscopy was defined as a GFR of less than 60 
mL/min and a decrease of at least 10 mL/min from the last value before 
colonoscopy, and/or at least a two-fold increase in creatinine from 
baseline within 6 months after colonoscopy. Patients with an 
identifiable, likely cause of renal impairment that was not clearly 
related to OSP or PEG use were excluded.
    Of a total of 2,352 eligible patients, 269 used PEG and 2,083 used 
OSP. Compared to the patients receiving OSP, those receiving PEG were 
on average older (>= 65 years of age), had a higher prevalence of heart 
failure, were using diuretics or an ARB, were more likely to have an 
inpatient colonoscopy procedure, and, in general, were more likely to 
be hospitalized during 12 months prior to the colonoscopy. The 
proportion of patients with mild renal impairment (GFR between 60 and 
90 mL/min) at baseline was similar between the OSP and PEG groups (49 
and 45 percent, respectively).

[[Page 7751]]

    A total of 88 patients were identified as having renal impairment 
after colonoscopy. The proportion of patients with renal impairment 
after colonoscopy was similar between OSP users (79/2083 (3.8 percent)) 
and PEG users (9/269 (3.3 percent)). Of these 88 cases, 50 patients had 
a GFR decrease of 20 mL/min, and 13 had at least a twofold increase in 
creatinine after colonoscopy. In 21 out of those 88 cases, GFR remained 
< 60 mL/min 6 months after colonoscopy, and out of these 17 had used 
OSP and 4 had used PEG. The relative risk (RR) estimate for renal 
impairment comparing OSP and PEG was 1.13 (95 percent confidence 
interval 0.58-2.23) without adjustment, and the Odds Ratio after 
multivariate adjustment was 1.14 (0.55-2.39). Significant risk factors 
were those identified by earlier studies and include age greater than 
or equal to 65, African American race, low baseline GFR, hypertension 
and use of ACE inhibitors, ARBs, or thiazide diuretics. The authors of 
the study concluded that in patients without preexisting kidney 
disease, the risk of kidney impairment after colonoscopy appears to be 
similar between OSP and PEG users.
    It is difficult to make definitive conclusions from this study for 
the following reasons:
    1. A significantly greater proportion of OSP users who underwent 
colonoscopy were excluded from the study, which may introduce a 
potential selection bias.
    2. There is a wide range of time between measurements of serum 
creatinine. Although the authors claimed that adjustment for 
differences in the latency time from colonoscopy to creatinine 
determination did not alter the risk estimates, analysis of such data 
was not provided.
    3. PEG users tended to have a higher prevalence of co-morbid 
conditions (e.g., congestive heart failure, liver cirrhosis) or used 
agents that potentially impair kidney perfusion.
    4. Two different criteria were used for identification of patients 
with renal impairment post colonoscopy.
    There are limitations in the design of all of the five studies 
discussed previously, such as the lack of a consistent definition of 
acute kidney injury and the exclusion of patients with baseline serum 
creatinine values above a threshold value. As a consequence, no 
definitive conclusions can be drawn from these studies, and additional 
studies are needed to further assess subclinical changes in kidney 
function.

C. Consensus Statement on Bowel Preparation Before Colonoscopy

    In 2006, a Joint Task Force from the American Society of Colon and 
Rectal Surgeons (ASCRS), the American Society for Gastrointestinal 
Endoscopy (ASGE), and the Society of American Gastrointestinal and 
Endoscopic Surgeons (SAGES) issued a consensus statement on bowel 
preparation before colonoscopy (Ref. 40). The task force performed a 
critical scientific review of the available data, which included 21 
randomized, controlled trials in the published literature. The scope of 
the task group consensus statement included not only the customary dose 
of OSP but also other treatment modalities for bowel preparation, 
including PEG. Both oral solutions and the tablet formulations of OSP 
were assessed.
    In their consensus statement the Task Force acknowledges the risks 
associated with the customary dose of OSP for bowel cleansing. The Task 
Force drew the following conclusions based on its evaluation of the 
data:
    1. The use of OSP for bowel preparation prior to a colonoscopy is 
associated with abnormalities in serum electrolytes and altered 
extracellular fluid volume, which can cause significant losses of both 
fluid and electrolytes in the stool, resulting in volume contraction 
and dehydration.
    2. Rarely adverse events such as nephrocalcinosis with acute kidney 
failure have occurred after use of OSP.
    3. OSP use has been shown to cause elevated blood urea nitrogen 
levels, decreased exercise capacity, increased plasma osmolality, 
hypocalcemia, and significant hyponatremia and seizures.
    4. Although usually asymptomatic, hyperphosphatemia is seen in as 
many as 40 percent of healthy patients completing OSP preparations, and 
hypokalemia developed in as many as 20 percent of patients using OSP 
preparations.
    The Task Force advised physicians to select a preparation for each 
patient based on the safety profile of the agent and the overall health 
of the patient, their comorbid conditions and currently prescribed 
medications. They further advised that in certain circumstances such as 
bowel preparation in children, the elderly, patients with renal 
insufficiency, and those with hypertension taking an ACE inhibitor or 
an ARB, it may be advisable to adhere to PEG-based solutions because of 
the risk of occult physiologic disturbances that may contraindicate the 
use of sodium phosphates regimens.

D. FDA's Tentative Conclusions on the Safety of Nonprescription Sodium 
Phosphate Oral Solutions for Bowel Cleansing

    FDA has tentatively concluded that the customary dose of OTC sodium 
phosphate salts for bowel cleansing (i.e., two 45-mL doses taken 12 
hours apart or a 45-mL dose followed by a 30-mL dose of sodium 
phosphates oral solution 10 to 12 hours later) in an OTC setting based 
on professional labeling in an OTC monograph poses an unacceptable risk 
of serious adverse events. Some patients have experienced sudden and 
severe acute kidney failure which may require kidney dialysis, while 
others have had a less serious course that resolves with minimal 
intervention. The outcome has varied from complete recovery to, in rare 
instances, death. Some patients may have residual kidney damage and may 
never return to the kidney function present prior to OSP use.
    Some of the retrospective studies that have reviewed the serum 
creatinine of large numbers of patients who underwent bowel preparation 
for colonoscopy at the customary OSP doses suggest that the percent of 
cases leading to serious injury with symptoms is relatively rare. 
However, there is no accurate estimate of the incidence of acute kidney 
injury in patients receiving these doses of OSP for bowel cleansing. 
Some studies have identified populations who appear to be at risk, but 
data from prospective studies are needed to better define the risk of 
acute kidney injury in patients using OSP at the current doses as 
preparation for colonoscopy and to determine the risk factors that may 
predispose patients to such injury.
    The study by Hurst also raises questions about the possible effects 
of small changes in serum creatinine that may occur after OSP use at 
the customary doses for bowel cleansing (Ref. 34). This is an important 
question that needs to be addressed. There are about 14 million 
screening colonoscopies per year in the United States., for which an 
estimated 50 percent will use OSP for bowel cleansing (Ref. 31). Given 
the magnitude of the exposure, the possibility of low grade declines in 
GFR after exposure to OSP is troubling when one considers that many 
patients undergo colonoscopies more than once in their lifetime and the 
damage that occurs with every exposure could be cumulative for some 
individuals. Other studies have not supported the findings of Hurst. 
Thus, it is important that this issue be addressed with clinical trials

[[Page 7752]]

using more exact measurements of glomerular filtration rate. For these 
reasons, FDA has required the NDA holder of prescription OSP products 
to conduct prospective, randomized, active-controlled clinical trials 
to determine the absolute and relative risk of kidney injury (including 
acute phosphate nephropathy) following the use of these products.
    Further, because of continuing reports of acute kidney injury 
associated with the prescription and customary dose of OTC OSP products 
for bowel cleansing, despite repeated educational efforts by FDA and 
the detailed professional labeling provided by a drug manufacturer for 
these products, we have tentatively concluded that OSP for bowel 
cleansing at the currently used doses poses a serious risk of adverse 
events in some patients. Therefore, additional measures are needed to 
manage the risk posed by this use of OSP products for bowel cleansing 
to assure that the benefits outweigh the potential risks. The need for 
these additional measures precludes the continued use of the current 
regimen of sodium phosphates oral solution for bowel cleansing under 
the professional labeling of an OTC monograph.
    Under the current professional labeling provisions of the 1985 TFM 
published on January 15, 1985 (50 FR 2124), consumers rely on their 
healthcare provider to provide information on the safe use of the 
sodium phosphates oral solution for bowel cleansing. This approach has 
not been sufficient to manage the risk that has been associated with 
the customary dose of OTC sodium phosphates oral solution for bowel 
cleansing. We believe that consumers need to have detailed information 
in the form of patient labeling and information from a physician 
regarding the safe use of the product. Risk information in patient 
labeling could affect patients' decisions to use these products, and 
thus help prevent serious adverse effects. This kind of patient 
labeling (see 21 CFR 201.57 and 21 CFR part 208) cannot be accomplished 
with professional labeling found in an OTC monograph. Professional 
labeling is labeling provided only to healthcare professionals who 
direct patients to use OTC products in ways that differ from the 
consumer labeling for these products. Manufacturers marketing OTC 
products under the 1985 TFM cannot provide consumers with labeling 
information on the OTC package related to those indications or uses 
that are not part of the drug facts labeling allowed under the 1985 
TFM. For all of these reasons, we are proposing in this document that 
the professional labeling for bowel cleansing use be removed from the 
tentative final monograph because of our safety concern with the bowel 
cleansing use of sodium phosphate products.
    We also believe that the safe use of OSP as presently used for 
bowel cleansing requires the continuing involvement of a doctor to 
monitor its effects on kidney function. Section 503(b)(1) of the FD&C 
Act establishes the standards under which the marketing of a drug must 
be limited to prescription. Among these is the need for collateral 
measures for the safe use of the product and the need for the 
involvement of a licensed practitioner to ensure the safe use of the 
product. For the reasons already given, the customary dose of OSP 
solution for bowel cleansing meets the statutory definition of a 
prescription product. Thus, in this document FDA proposes to classify 
OTC sodium phosphate salts, singly or in combination with each other, 
as not GRAS (i.e., nonmonograph) for the professional labeling 
indication proposed in the 1985 TFM, i.e., ``For use as part of a bowel 
cleansing regimen in preparing the patient for surgery or for preparing 
the colon for x-ray endoscopic examination.'' This proposed rule would 
amend Sec.  310.545 to include sodium phosphate salts for bowel 
cleansing use, as described in Sec.  334.80 of the 1985 TFM, as 
nonmonograph.
    Screening colonoscopy can lead to the early detection of colon 
cancer and polyps, which, if not removed, can progress to cancer. Early 
detection of colon cancer can result in more effective treatment and a 
survival advantage. Inadequate preparation for colonoscopy can lead to 
missed lesions. OSP products have been shown to be effective in 
cleansing the colon, thereby allowing better visualization of cancers 
and polyps. FDA believes it is important to have multiple options 
available for bowel cleansing because no single product is tolerated by 
all individuals. It is important, however, to make sure that the risk 
for serious injury is very low and the appropriate populations are 
identified who can use these products safely.

IV. FDA's Tentative Conclusions on the Safety and Effectiveness of 
Other Doses of Sodium Phosphates Oral Solution for Bowel Cleansing

    FDA has previously acknowledged the effectiveness of the bowel 
cleansing regimen that is currently the standard of practice for OTC 
sodium phosphates oral solution, i.e., 60-g sodium phosphate 
administered in two 45-mL doses of sodium phosphates oral solution 
taken 10 to 12 hours apart (Ref. 14). However, the available data raise 
serious concerns about the safety of this regimen.
    There are some data that suggest a lower sodium phosphate dose may 
be similar in effectiveness to the regimen currently in use. An 
unpublished study comparing the effectiveness of sodium phosphates oral 
solution at two dose levels, the standard 2 x 45-mL dose (60 g sodium 
phosphate) and a reduced 2 x 30-mL dose (37 g sodium phosphate), with 
PEG solution was included in a citizen petition from a manufacturer of 
sodium phosphate laxative products (Ref. 18). The study, PS-9902, was a 
randomized, single-blind, parallel group design. The two regimens were 
administered as divided doses 10 to 12 hours apart. A total of 238 
subjects were randomized to one of the three treatments. Seventy-four 
subjects took the 2 x 45-mL dose, and 75 subjects took the 2 x 30 mL 
dose. There were 73 subjects who took PEG. The study excluded all 
patients with current labeling contraindications to OSP use and all 
patients for whom use is allowed with caution.
    The manufacturer's evaluation of physicians' assessments of bowel 
preparation indicated no statistically significant differences between 
the 2 x 30-mL sodium phosphates oral solution group and the PEG group 
for any of the effectiveness endpoints: Residual stool, stool 
consistency, and bowel wall visualization parameters. Bowel cleansing 
with the two 45-mL doses was found to be superior to the lower dose OSP 
regimen and PEG. The observed electrolyte changes and side effects were 
milder with the two 30-mL doses of OSP compared to the two 45-mL dose. 
Elevation in serum sodium was the only significant electrolyte change 
between the OSP groups. Four patients on the two 45-mL dose regimen had 
post-prep sodium levels that exceeded the upper limit of normal but 
remained below 150 millimole/Liter.
    While the results of this study are worth noting, they are not 
sufficient to demonstrate the safety and effectiveness of the reduced 
phosphate regimen. It is noteworthy that 32 percent (23/73) of the PEG 
subjects reported that they did not complete the treatment regimen. 
This finding may have reduced the efficacy found in the PEG group, 
thereby minimizing treatment effect differences between PEG and the low 
dose phosphate regimen. There were also irregularities in 
randomization. Ten patients were excluded following randomization, 
because they were randomized before all inclusion criteria were 
verified. In addition, at one study

[[Page 7753]]

site, six patients were randomized out of order and did not receive the 
treatments assigned by the randomization protocol. Thus, the study 
results can not be considered a conclusive demonstration of the 
effectiveness of these products. In addition, while the electrolyte 
changes and side effects were milder with the two 30-mL doses of sodium 
phosphates oral solution, the number of subjects exposed to the 
proposed lower dose regimen (79 subjects) is too small to allow any 
conclusions about the safety of the lower dose regimen.

V. Summary of Significant Changes From the 1985 Proposed Rule for OTC 
Laxative Drug Products

    1. FDA is classifying sodium phosphate salts described in Sec.  
334.16(d), (e) and (f), as nonmonograph and removing them as acceptable 
active ingredients for the use as a bowel cleansing agent described in 
Sec.  334.80(a)(2).
    2. FDA is removing the warning in Sec.  334.80(b)(2) for sodium 
phosphate salts. The warning will be revised and included in a proposed 
rule to be published at a future date.

VI. Proposed Effective Date

    The existing evidence is inadequate to establish the safety of OTC 
sodium phosphate salts (dibasic sodium phosphate, monobasic phosphate 
and dibasic sodium phosphate/monobasic sodium phosphate (sodium 
phosphates) solution) for professional use as a bowel cleansing 
preparation prior to surgery or endoscopic examination. Accordingly, 
sodium phosphate salts cannot be considered GRAS for OTC use for bowel 
cleansing.
    If this proposal becomes a final rule, the conditions under which 
drug products subject to this rule are not GRASE and are misbranded 
will be effective 30 days after the date of the final rule's 
publication in the Federal Register. On or after that date, any OTC 
laxative products containing dibasic sodium phosphate or monobasic 
phosphate and dibasic sodium phosphate/monobasic sodium phosphate 
(sodium phosphates) marketed for bowel cleansing will be misbranded and 
will require an approved NDA for bowel cleansing use and marketing. Any 
OTC drug product subject to the final rule that is repackaged or 
relabeled after the effective date of the final rule must be in 
compliance with the final rule, regardless of the date the product was 
initially introduced or initially delivered for introduction into 
interstate commerce.

VII. Analysis of Impacts

    FDA has examined the impacts of the proposed rule under Executive 
Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-612), and the 
Unfunded Mandates Reform Act of 1995 (Pub. L. 104-4). 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). The agency believes that 
this proposed rule is not a significant regulatory action as defined by 
the Executive order.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because this proposed rule only affects labeling 
provided to healthcare professionals for the indication of bowel 
cleansing and does not affect the marketing of sodium phosphates oral 
solution for consumer use as a laxative for the relief of occasional 
constipation, the agency proposes to certify that the final rule will 
not have a significant economic impact on a substantial number of small 
entities.
    Section 202(a) of the Unfunded Mandates Reform Act of 1995 requires 
that agencies prepare a written statement, which includes an assessment 
of anticipated costs and benefits, before proposing ``any rule that 
includes any Federal mandate that may result in the expenditure by 
State, local, and Tribal governments, in the aggregate, or by the 
private sector, of $100,000,000 or more (adjusted annually for 
inflation) in any one year.'' The current threshold after adjustment 
for inflation is $135 million, using the most current (2009) Implicit 
Price Deflator for the Gross Domestic Product. FDA does not expect this 
proposed rule to result in any 1-year expenditure that would meet or 
exceed this amount.
    The purpose of this proposed rule is to remove the professional 
labeling relating to the use of sodium phosphates oral solution 
laxatives for bowel cleansing in the 1985 TFM (50 FR 2124 at 2157). 
Professional labeling is information directed to health professionals 
who prescribe, administer, or dispense medications, and may not be 
included in labeling directed to the consumer. This proposed rule 
amends Sec.  334.80 to remove the bowel cleansing indication for sodium 
phosphates oral solution laxatives based on concerns about serious 
adverse reactions associated with the use of these OTC drug products in 
preparation for colonoscopy and x-ray before surgery.

A. Background

    FDA has taken a number of measures to mitigate the risk of serious 
adverse events associated with the use of OSP products in preparation 
for colonoscopy and x-ray endoscopic examination. As discussed in the 
preamble, FDA has limited the acceptable container sizes that can be 
marketed and added warnings and direction statements to OTC sodium 
phosphates solutions marketed for laxative and to healthcare 
professionals for bowel cleansing use. Separate from this proposed 
rule, the agency has also made several attempts to educate and alert 
both healthcare professionals and consumers about potential risks 
associated with customary dose of OSP products for bowel cleansing. 
Despite these measures, FDA's AERS has continued to receive reports of 
acute kidney injury that have been associated with the customary dose 
of OSP products for bowel cleansing.
    For this reason, on December 12, 2008, FDA took steps to limit the 
marketing of OSP products for bowel cleansing to prescription only and 
to increase the prominence of risk information by requiring a boxed 
warning on prescription OSP products (Ref. 1). In addition, the 
continued marketing of prescription OSP products will require the 
development of a risk evaluation and mitigation strategy that includes 
the development of a Medication Guide and a communication strategy 
targeted at healthcare providers who are likely to prescribe OSP 
products. FDA has also instructed the holders of NDAs for OSP products 
to conduct prospective clinical trials to assess the risk of acute 
kidney injury in patients using sodium phosphate products for bowel 
cleansing and to better define the risk factors that predispose 
patients to such injury. FDA has taken these steps in an attempt to 
increase the level of risk communication for these products and thereby 
reduce the incidence of adverse events that has been associated with 
these products.

B. Need for the Proposed Rule

    This proposed rule is consistent with the Agency's determination 
that the customary dose of OSP products for bowel cleansing (i.e., 
approximately 60 g of sodium phosphates taken as two 45-mL doses 12 
hours apart or approximately 50 g of sodium phosphates taken as a 45-mL 
dose followed by a 30-mL dose 12 hours later) poses a serious risk to 
some individuals and that the marketing of

[[Page 7754]]

these products for bowel cleansing should be limited to prescription 
only. In this document FDA proposes to classify OTC sodium phosphate 
salts, singly or in combination with each other, as not GRAS (i.e., 
nonmonograph) for bowel cleansing. Furthermore, FDA is proposing to 
remove professional labeling for bowel cleansing use from the 
monograph. Manufacturers of OTC OSP laxative products would no longer 
be able to promote the use of these products to healthcare 
professionals for bowel cleansing use. Consequently, the marketing of 
sodium phosphates oral solution marketed under an OTC drug monograph 
would be limited to laxative use at a lower sodium phosphates dose to 
relieve occasional constipation.

C. Impact of the Proposed Rule

    Executive Order 12866 and OMB Circular A-4 direct agencies to 
consider and provide a description of any important distributional 
effects that might be attributed to a regulation, where applicable. To 
the extent that OTC OSP products for bowel preparation remain on the 
market, this rule would shift those sales to prescription products 
only. Any such shift in sales represents a transfer payment between 
manufacturers within the industry and is not a social cost of this 
rule. The agency believes that most of this transfer has already 
occurred through voluntary withdrawal of OTC products by their 
manufacturers.
    An informal in-store review of several national drug and mass 
merchandise stores found that there were no OTC liquid OSP products on 
those store shelves. Pharmacists indicated that OSP liquid products 
were removed from the shelves in response to information from FDA. 
Therefore, the agency believes that any shift in sales from OTC to 
prescription products for bowel cleansing that would have been 
attributed to this rule most likely has already occurred.
    According to proprietary data from A.C. Nielsen, annual retail 
sales for OSP products totaled about $30 million in 2006. The vast 
majority of these sales are attributed to one manufacturer. That 
manufacturer has already voluntarily removed its OSP laxative products 
from the shelves. We believe that other suppliers have similarly 
removed their products. The agency requests specific comments on this 
assumption.
    To the extent that any OSP products for laxative use might remain 
on the market, there would be no relabeling or reformulation costs 
attributed to this rule. If, however, manufacturers have chosen to 
improperly label their OSP products with a bowel cleansing indication, 
these manufacturers will incur the cost of relabeling to remove the 
bowel cleansing use from their labels. These costs would be incurred 
without this rule, because professional uses of OTC drugs are not 
properly included in labeling directed to consumers.
    We analyzed proprietary data from SDI Health on the total number of 
retail prescriptions dispensed for bowel preparation products from 
March 2004 through February 2009. We included PEG products and OSP 
products that are considered alternatives to the OTC OSP products for 
bowel cleansing. The number of prescriptions for PEG products has grown 
significantly over this time period, whereas the number of OSP products 
remained relatively constant over most of this period and began to 
decline in late 2008. The average annual growth rate for all 
prescription bowel preparation products was 17 percent from 2006 to 
2008. From 2006 through the third quarter of 2008, the monthly share of 
sodium phosphate prescriptions dispensed for bowel preparation was 
about 13 to 15 percent of total prescriptions, but declined to a 
monthly low of 7 percent by February 2009. This apparent decline in 
dispensed prescription sodium phosphate products may be a market 
response to recent agency actions, including the boxed warning 
requirement, that are separate from this rule. However, it is too soon 
to determine market changes. Nonetheless, the data on the number of 
prescriptions dispensed suggest that prior agency actions may have had 
a dampening market effect on the use of OSP products for bowel 
preparation.

D. Benefits of the Proposed Rule

    Section III.A of this document presents data on the reports of 
serious adverse events associated with prescription and OTC products 
containing sodium phosphates for bowel cleansing. More than 100 adverse 
events have been reported that are associated with the customary dose 
of OSP products as presented in section III. A of this document. 
Although these serious events are rare, the public health consequences 
can be substantial. Acute phosphate nephropathy that has been 
associated with the customary dose of OSP for bowel cleansing can 
result in permanent impairment of kidney function that ultimately may 
require chronic dialysis or kidney transplant, and may result in long 
term renal failure and, in rare instances, death.
    The economic consequences of this severity of renal impairment are 
significant. The cost of hospitalization resulting from acute renal 
failure without dialysis has been estimated at $22,251 (51 FR 77314 at 
77344, December 26, 2006). Recent analyses have reported Medicare 
payments for a year's treatment of a dialysis patient of about $67,000. 
Employer group health insurance costs are much higher at $180,000 per 
year (Ref. 41).
    Estimates of the cost of kidney transplants also vary. Associated 
medical costs for transplants average about $102,000 in the year of the 
transplant (Ref. 42). The mean cost of hospitalization for a kidney 
transplant procedure was $128,000 in 2006 (Ref. 43). In addition, 
patients with kidney transplants require immunosuppressive drugs for 
years after their transplant.
    We believe, based on the available data, that sodium phosphates 
solution marketed under an OTC drug monograph for bowel cleansing may 
be a significant cause of severe adverse events. However, we note that 
there is uncertainty about the baseline risk of serious adverse events 
associated with customary dose of OSP products (for both OTC and 
prescription uses). It is not possible to predict a specific level of 
reduction in the incidence of these serious adverse events that might 
be attributable to limiting OSP products for bowel cleansing use to 
prescription drug use. Moreover, to the extent that OSP products have 
been voluntarily withdrawn from the market, this rule would not have an 
impact on the incidence of these serious adverse events.

E. Alternatives

    The agency considered but rejected several alternatives: (1) 
Requiring additional (OTC or professional) labeling that describes 
potential adverse effects, the subpopulations at greatest risk, and 
detailed directions about hydration, (2) a longer implementation period 
for this rule if finalized, and (3) product withdrawal, including 
prescription use. We do not believe that the first two alternatives to 
the proposed regulation would be adequate to provide for the safe use 
of OTC sodium phosphates oral solution for bowel cleansing (e.g., 
preparation for colonoscopy). Various attempts at conveying the risk 
associated with OTC sodium phosphates oral solution products, including 
detailed professional labeling describing potential adverse events and 
at risk populations (Ref. 29) by a manufacturer of an OTC sodium 
phosphates oral solution product have not been successful in reducing 
the number of serious adverse events attributed to these products. The 
agency also

[[Page 7755]]

considered but rejected a longer implementation period for this 
proposed rule if finalized, because of the overriding safety 
considerations. We rejected the third alternative, to withdraw the 
product, because OSP has been demonstrated to be effective for bowel 
cleansing, and we believe that it is important to continue to have 
multiple options available for bowel cleansing because no single 
product is tolerated by all individuals.

F. Impact on Small Businesses

    The Small Business Administration (SBA) defines an entity as small 
in the pharmaceutical manufacturing industry if the business has fewer 
than 750 employees. Over 90 percent of manufacturers in the OTC 
pharmaceutical industry are classified as small. To the extent that 
there continue to be manufacturers of OSP products for bowel 
preparation that remain on the market, those sales would be shifted to 
prescription products. This is a transfer payment and not a social cost 
of this rule. The agency believes that most of this impact has already 
occurred with manufacturers voluntarily withdrawing products from the 
market prior to this rule.
    We estimate that there are about 10 manufacturers that could be 
affected by this proposed rule and that all of them are small 
businesses. The economic impact on any remaining individual firms will 
vary based on the amount of lost production and lost sales revenue that 
is derived from sales of the OSP products for bowel cleansing. Without 
knowing the volume of OTC OSP sales that can be attributed to this use, 
it is difficult to estimate the impact of this proposed rule on small 
business entities. As noted above, a major manufacturer of OTC OSP 
labeled for professional use for bowel cleansing has already 
voluntarily withdrawn its bowel cleansing products from the market. The 
remaining suppliers may have done the same.
    Given the small number of manufacturers of these products, we 
believe that it is unlikely that this proposed rule will have a 
significant economic impact on a substantial number of small entities. 
Nonetheless, the agency requests detailed comments on small businesses 
impacts. The proposed rule will not require any new recordkeeping and 
no additional professional skills are needed.
    This analysis shows that this proposed rule is not economically 
significant under Executive Order 12866. 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 Reform Act does not apply to this 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 $135 million.
    FDA invites public comment regarding any significant economic 
impact that this proposal would have on affected manufacturers of 
sodium phosphates oral solutions. Comments regarding the impact of this 
proposal should be accompanied by appropriate documentation. FDA will 
evaluate any comments and supporting data that are received and will 
reassess the economic impact of this rulemaking in the preamble to any 
final rule.

VIII. Paperwork Reduction Act of 1995

    This proposed rule contains no collections of information. 
Therefore, clearance by the Office of Management and Budget under the 
Paperwork Reduction Act of 1995 is not required.

IX. Environmental Impact

    FDA has determined under 21 CFR 25.31(a) 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.

X. Federalism

    We have analyzed this proposed rule in accordance with the 
principles set forth in Executive Order 13132. Section 4(a) of the 
Executive order requires agencies to ``construe * * * a Federal statute 
to preempt State law only where the statute contains an express 
preemption provision or there is some other clear evidence that the 
Congress intended preemption of State law, or where the exercise of 
State authority conflicts with the exercise of Federal authority under 
the Federal statute.'' The sole statutory provision giving preemptive 
effect to the proposed rule is section 751 of the FD&C Act (21 U.S.C. 
379r).
    We believe that the preemptive effect of this proposed rule, if 
finalized, would be consistent with Executive Order 13132. Through the 
publication of this proposed rule, we are providing notice and an 
opportunity for State and local officials to comment on this 
rulemaking.

XI. References

    The following references are on display in the Division of Dockets 
Management (HFA-305), 5630 Fishers Lane, rm. 1061, Rockville, MD 20852, 
under Docket No. FDA-1978-N-0021 (formerly Docket No. 78N-036L) and may 
be seen by interested persons between 9 a.m. and 4 p.m., Monday through 
Friday.
    1. Document Id. FDA-2007-P-0345-0003, Federal Dockets Management 
System.
    2. Document Id. FDA-2007-P-0345-0005, Federal Dockets Management 
System.
    3. Comment No. CP8, Docket 1978N-036L, Division of Dockets 
Management.
    4. Comment No. SUP5, Docket No. 1978N-036L, Division of Dockets 
Management.
    5. Comment No. LET41, Docket No. 1978N-036L, Division of Dockets 
Management.
    6. Document Id. FDA-1978-N-0021-0032-0036, Federal Dockets 
Management System.
    7. Comment No. CP14, Docket No. 1978N-036L, Division of Dockets 
Management.
    8. Comment No. SUP8, Docket No. 1978N-036L, Division of Dockets 
Management.
    9. Comment No. AMD10, Docket No. 1978N-036L, Division of Dockets 
Management.
    10. Comment No. LET71, Docket No. 1978N-036L, Division of Dockets 
Management.
    11. Comment No. SUP11, Docket No. 1978N-036L, Division of Dockets 
Management.
    12. Comment No. SUP10, Docket No. 1978N-036L, Division of Dockets 
Management.
    13. Comment No. C146, Docket No. 1978N-036L, Division of Dockets 
Management.
    14. Comment No. LET109, Docket No. 1978N-036L, Division of Dockets 
Management.
    15. Comment No. PDN4, Docket No. 1978N-036L, Division of Dockets 
Management.
    16. Comment No. CP1, Docket No. 00P-1472, Division of Dockets 
Management.
    17. Comment No. PDN1, Docket No. 00P-1472, Division of Dockets 
Management.
    18. Comment No. CP28, Docket No. 1978N-036L, Division of Dockets 
Management.
    19. Comment No. LET204, Docket No. 1978N-036L, Division of Dockets 
Management.
    20. Document Id. FDA-1978N-0021-0031, Federal Dockets Management 
System.
    21. Comment No. C207, Docket No. 1978N-036L, Division of Dockets 
Management.

[[Page 7756]]

    22. Comment No. C208, Docket No. 1978N-036L, Division of Dockets 
Management.
    23. Comment No. SUP18, Docket No. 1978N-036L, Division of Dockets 
Management.
    24. FDA Science Background Paper: ``Safety of Sodium Phosphates 
Oral Solution'' September 17, 2001 in OTC Volume 09OSPPR.
    25. FDA Science Background Paper: ``Acute Phosphate Nephropathy and 
Renal Failure Associated with the Use of Oral Sodium Phosphate Bowel 
Cleansing Products,'' May 2006 in OTC Volume 09OSPPR.
    26. FDA Information for Healthcare Providers: Oral Sodium Phosphate 
Products for Bowel Cleansing, May 2006 in OTC volume 09OSPPR.
    27. FDA Alert: Oral Sodium Phosphate (OSP) Products for Bowel 
Cleansing (marketed as Visicol and OsmoPrep, and oral sodium phosphate 
products available without a prescription), December 11, 2008 in OTC 
volume 09OSPPR.
    28. FDA Information for Healthcare Professionals: Oral Sodium 
Phosphate (OSP) Products for Bowel Cleansing (marketed as Visicol and 
OsmoPrep, and oral sodium phosphate products available without a 
prescription), December 11, 2008, in OTC volume 09OSPPR.
    29. Professional Labeling for Fleets Phosphasoda in OTC volume 
09OSPPR.
    30. Khurana, A. et al., ``Acute Phosphate Nephropathy,'' Journal of 
the American Society of Nephrology, 17: 163A, 2006.
    31. Markowitz, G. S. et al., ``Acute Phosphate Nephropathy 
Following Oral Sodium Phosphate Bowel Purgative: An Unrecognized Cause 
of Chronic Renal Failure,'' Journal of the American Society of 
Nephrology, 16:3389-3396, 2005.
    32. Ma, R. C. et al., ``Acute Renal Failure Following Oral Sodium 
Phosphate Bowel Preparation in Diabetes,'' Diabetes Care, January: 
30(1):182-3. 2007.
    33. Gonlusen, G. et al., ``Renal Failure and Nephrocalcinosis 
Associated with Oral Sodium Phosphate Bowel Cleansing: Clinical 
Patterns and Renal Biopsy Findings,'' Archives of Pathology and 
Laboratory Medicine, January: 130(1):101-6, 2006.
    34. Hurst, F. P. et al., ``Association of Oral Sodium Phosphate 
Purgative Use with Acute Kidney Injury,'' Journal of the American 
Society of Nephrology, 18:1-6, 2007.
    35. Brunelli, S. M. et al., ``Risk of Kidney Injury Following Oral 
Phoshphasoda Bowel Preparations,'' Journal of the American Society of 
Nephrology, 18: 199-3205, 2007.
    36. Abaskharoun, R., W. Depew, and S. Vanner, ``Changes in Renal 
Function Following Administration of Oral Sodium Phosphate or 
Polyethylene Glycol for Colon Cleansing Before Colonoscopy,'' Canadian 
Journal of Gastroenterology, April: 21(4):227-31, 2007.
    37. Khurana A., L. McLean, S. Atkinson, and C. J. Foulks, ``The 
Effect of Oral Sodium Phosphate Drug Products on Renal Function in 
Adults Undergoing Bowel Endoscopy,'' Archives of Internal Medicine, 
March 24:168(6):593-7, 2008.
    38. Levey, A. S., T. Greene, J. Kusek, and G. Beck, ``A Simplified 
Equation to Predict Glomerular Filtration Rate from Serum Creatinine 
(abstract), Journal of the American Society of Nephrology, 11: p.155A, 
2000.
    39. Russman, S. et al., ``Risk of Impaired Renal Function After 
Colonoscopy: A Cohort Study in Patients Receiving Either Oral Sodium 
Phosphate or Polyethylene Glycol,'' American Journal of 
Gastroenterology, 102:2655-2663, 2007.
    40. Wexner, S.D. et al., ``A Consensus Document on Bowel 
Preparation Before Colonoscopy,'' prepared by a task force from the 
American Society of Colon and Rectal Surgeons (ASCRS), the American 
Society for Gastrointestinal Endoscopy (ASGE), and the Society of 
American Gastrointestinal and Endoscopic Surgeons (SAGES), 
Gastrointestinal Endoscopy; 63:894-909, 2006.
    41. Just, P. M. et al., ``Reimbursement and Economic Factors 
Influencing Dialysis Modality Choice around the World,'' Nephrology 
Dialysis Transplantation, 23(7):2365-2373, 2008.
    42. St. Peter, W., ``Introduction: Chronic Kidney Disease: A 
Burgeoning Health Epidemic,'' Journal of Managed Care Pharmacy, 
13(9):S2-S5, 2007.
    43. Agency for Healthcare Research and Quality, HCUPnet National 
and regional estimates on hospital use for all patients from the HCUP 
Nationwide Inpatient Sample (NIS) (2006), data accessed March 11, 2009.

List of Subjects

21 CFR Part 310

    Administrative practice and procedure, Drugs, Labeling, Medical 
devices, Reporting and recordkeeping requirements.

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 parts 310 and 334 (as proposed in the Federal 
Register of January 15, 1985 (50 FR 2124)), October 1, 1986 (51 FR 
35136), September 2, 1993 (58 FR 46589), March 31, 1994 (59 FR 15139), 
September 2, 1997 (62 FR 46223), May 21, 1998 (63 FR 27886), June 19, 
1998 (63 FR 33592), March 24, 2004 (69 FR 13765), November 29, 2004 (69 
FR 69278), be amended as follows:

PART 310--NEW DRUGS

    1. The authority citation for 21 CFR part 310 continues to read as 
follows:

    Authority:  21 U.S.C. 321, 331, 351, 352, 353, 355, 360b-360f, 
360j, 361(a), 371, 374, 375, 379e; 42 U.S.C. 216, 241, 242(a), 262, 
263b-263n.

    2. Section 310.545 is amended by redesignating paragraph 
(a)(12)(ii) as paragraph (a)(12)(ii)(A), by adding paragraph 
(a)(12)(ii)(B), by revising paragraph (d) introductory text and 
paragraph (d)(1), and by adding paragraph (d)(53) to read as follows:

Sec.  310.545  Drug products containing certain active ingredients 
offered over-the-counter (OTC) for certain uses.

    (a) * * *
    (12) * * *
    (ii) * * *
    (B) Saline laxatives--Approved as of [INSERT DATE 30 DAYS AFTER 
DATE OF PUBLICATION OF THE FINAL RULE IN THE FEDERAL REGISTER].

Dibasic sodium phosphate, monobasic sodium phosphate, and sodium 
phosphates (dibasic sodium phosphate monobasic sodium phosphates in a 
solution dosage form administered as 59.4 grams (g) of sodium 
phosphates taken in two 45-milliter (mL) doses 12 hours apart or 49.5 g 
of sodium phosphates taken as a 45-mL dose followed by a 30-mL dose 12 
hours later) for use as part of a bowel cleansing regimen in preparing 
the patient for surgery or for preparing the colon for x-ray endoscopic 
examination.
* * * * *
    (d) Any OTC drug product that is not in compliance with this 
section is subject to regulatory action if initially introduced or 
initially delivered for introduction into interstate commerce after the 
dates specified in paragraphs (d)(1) through (d)(53) of this section.
    (1) May 7, 1991, for products subject to paragraphs (a)(1) through 
(a)(2)(i), (a)(3)(i), (a)(4)(i), (a)(6)(i)(A), (a)(6)(ii)(A), (a)(7) 
(except as covered by paragraph (d)(3) of this section), (a)(8)(i), 
(a)(10)(i) through (a)(10)(iii), (a)(12)(i)(A), (a)(12)(ii)(A), 
(a)(12)(iii), (a)(12)(iv)(A), (a)(14) through (a)(15)(i),

[[Page 7757]]

(a)(16) through (a)(18)(i)(A), (a)(18)(ii) (except as covered by 
paragraph (d)(22) of this section), (a)(18)(iii), (a)(18)(iv), 
(a)(18)(v)(A), and (a)(18)(vi)(A) of this section.
* * * * *
    (53) [INSERT DATE 30 DAYS AFTER DATE OF PUBLICATION OF THE FINAL 
RULE IN THE FEDERAL REGISTER], for products subject to paragraph 
(a)(12)(ii)(B) of this section.

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

    3. 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.

Sec.  334.80  [Amended]

    4. Section 334.80 as proposed on January 15, 1985 (50 FR 2124), is 
amended by removing ``sodium phosphate/sodium biphosphate identified in 
Sec.  334.16(d)'' from paragraph (a)(2), and by removing paragraph 
(b)(2) and redesignating paragraph (b)(3) as paragraph (b)(2).

    Dated: February 3, 2011.
Leslie Kux,
Acting Assistant Commissioner for Policy.
[FR Doc. 2011-3091 Filed 2-10-11; 8:45 am]
BILLING CODE 4160-01-P