Professional Labeling for Laxative Drug Products for Over-the-Counter Human Use:

 
CONTENT

Federal Register: February 11, 2011 (Volume 76, Number 29)

Proposed Rules

Page 7743-7757

From the Federal Register Online via GPO Access [wais.access.gpo.gov]

DOCID:fr11fe11-15

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.

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

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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

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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.''

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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

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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.

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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

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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 = 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).

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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