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§ 330.17 Deposit insurance training. (d) Definitions. (1) Account shall drug that is directed to healthcare (a) Purpose. The purpose of this mean a deposit account at a depository professionals who prescribe, administer, section is to maintain confidence in institution that is held by or offered to or dispense medications and is not Federally insured depository a customer. It includes time, demand, included in OTC drug product labeling institutions and to protect depositors by savings, and negotiable order of for consumers. FDA is issuing this requiring insured depository institution withdrawal accounts. The term does not proposed rule after a careful review of employees with authority to open include a fiduciary account as to which new data and information on the serious accounts and/or respond to customer the insured depository institution does side effects that have been associated inquiries regarding deposit insurance not, in the normal course of business, with the customary dose of OTC sodium coverage (‘‘employees’’), to complete keep records of beneficial owners of the phosphates solution (approximately 60 training on basic deposit insurance deposits in the account. grams (g) of sodium phosphates taken in principles once in any twelve month (2) New Account shall mean any two 45-milliliter (mL) doses 12 hours period. New employees must complete deposit account at an insured apart or approximately 50 g of sodium the training within 30 days of depository institution to which the phosphates taken in a 45-mL dose commencing employment. Current insured depository institution assigns a followed by a 30-mL dose 12 hours employees are required to complete the unique identifier that serves to later) for bowel cleansing prior to training within 60 days of the effective distinguish the account from other, colonoscopy. This proposed rule is part date of the final rule. existing accounts at the depository of FDA’s ongoing review of OTC drug (b) Applicability. The requirements in institution. products. this section shall apply to all insured By order of the Board of Directors. DATES: Submit electronic or written depository institution employees who Dated at Washington, DC, this 7th day of comments by March 14, 2011. See have the authority to open accounts February, 2011. section VI of this document for the and/or respond to customer inquiries Federal Deposit Insurance Corporation. effective date of any final rule that may regarding deposit insurance coverage. Robert E. Feldman, publish based on this proposal. (c) Procedure. (1) Insured Depository ADDRESSES: You may submit comments, Institution Personnel Education. (i) Executive Secretary. [FR Doc. 2011–3085 Filed 2–10–11; 8:45 am] identified by Docket No. FDA–1978–N– Training. An insured depository 0021 (formerly Docket No. 78–N–036L) BILLING CODE 6714–01–P institution must require each employee and RIN number 0910–AF38, by any of with the authority to open accounts the following methods: and/or respond to customer inquiries regarding deposit insurance coverage to DEPARTMENT OF HEALTH AND Electronic Submissions complete basic deposit insurance HUMAN SERVICES Submit electronic comments in the training annually, using an FDIC- following way: Food and Drug Administration provided training module. Each new • Federal eRulemaking Portal: http:// employee with the authority to open www.regulations.gov. Follow the 21 CFR Parts 310 and 334 accounts and/or respond to customer instructions for submitting comments. inquiries regarding deposit insurance [Docket No. FDA–1978–N–0021; Formerly coverage must be required to undergo Docket No. 78N–036L] Written Submissions such training within 30 days of Submit written submissions in the commencing employment. RIN 0910–AF38 following ways: (ii) Training Materials. The FDIC will • Professional Labeling for Laxative FAX: 301–827–6870. provide the training module in the form • Drug Products for Over-the-Counter Mail/Hand delivery/Courier (For of a self-administered computer-based Human Use; Proposed Amendment to paper, disk, or CD–ROM submissions): instructional program. the Tentative Final Monograph Division of Dockets Management (HFA– (2) Ascertaining Insured Status. An 305), Food and Drug Administration, insured depository institution must AGENCY: Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, implement procedures so that, HHS. MD 20852. whenever a customer opens a new ACTION: Proposed rule. Instructions: All submissions received deposit account at an insured must include the agency name, docket depository institution, the employee SUMMARY: The Food and Drug number (Docket No. FDA–1978–N– opening the account shall inquire Administration (FDA) is issuing a 0021) (formerly Docket No. 78N–036L) whether the customer has an ownership proposed rulemaking to amend the and Regulatory Information Number interest in any other accounts at the IDI tentative final monograph (1985 TFM) (RIN) (RIN 0910–AF38) for this and, if so, whether the customer’s for over-the-counter (OTC) laxative drug rulemaking. All comments received may aggregate ownership interest in deposit products (products that relieve be posted without change to http:// accounts, including the new account, occasional constipation). FDA is www.regulations.gov including any exceeds the Standard Maximum Deposit proposing that sodium phosphate salts personal information provided. For Insurance Amount. If the customer (dibasic sodium phosphate, monobasic additional information on submitting responds affirmatively, then the IDI sodium phosphate, and the combination comments, see the ‘‘Comments’’ heading employee shall provide the customer of dibasic sodium phosphate/monobasic of the SUPPLEMENTARY INFORMATION with the FDIC’s Deposit Insurance sodium phosphate salts in a solution section of this document. Summary publication. In the case of dosage form) are not generally Docket: For access to the docket, to deposit accounts opened by mail or via recognized as safe (GRAS) for bowel read background documents or the Internet or other technology, these cleansing. This document also would comments received, go to http:// inquiries can be included in the paper withdraw the professional labeling www.regulations.gov and insert the or electronic application form, with the proposed for sodium phosphate salts in docket number, found in brackets in the link to the Deposit Insurance Summary the 1985 TFM. Professional labeling is heading of this document, into the publication provided. additional information about an OTC ‘‘Search’’ box and follow the prompts

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and/or go to the Division of Dockets Biologic plausibility means a causal cleansing is approximately 60 g of Management, 5630 Fishers Lane, Rm. association (or relationship between two sodium phosphates (dibasic sodium 1061, Rockville, MD 20852. factors) that is consistent with existing phosphate and monobasic sodium FOR FURTHER INFORMATION CONTACT: medical knowledge. phosphate salts) solution taken orally as Mary S. Robinson, Center for Drug Bowel cleansing means clearing the two 45-mL doses 12 hours apart or Evaluation and Research, Food and lower digestive tract in preparation for approximately 50 g of sodium Drug Administration, 10903 New a colonoscopy. phosphates taken as a 45-mL dose Hampshire Ave., Bldg. 22, MS5411, Bowel cleansing system means a followed by a 30-mL dose 12 hours Silver Spring, MD 20993–0002, 301– laxative product containing a later. In the tentative final monograph 796–2090. combination of several different laxative for OTC laxative drug products ingredients for sequential published January 15, 1985 (50 FR SUPPLEMENTARY INFORMATION: administration at specified intervals for 2124), FDA proposed labeling for Table of Contents use in cleansing the bowel prior to healthcare professionals for the use of I. Glossary surgery, colon x-ray, or endoscopic OTC sodium phosphates solution for II. Background examination. bowel cleansing. Subsequently, FDA A. Purpose of the Rule Electrolyte disturbance means approved sodium phosphates tablets for B. Chronology of the Federal Register abnormal levels of electrolytes such as prescription use for bowel cleansing Publications Addressing Professional sodium, potassium, calcium, or through the new drug application (NDA) Labeling for Sodium Phosphate Salts in phosphorous found in the blood and approval process. However, over the the OTC Laxative Drug Products other body fluids. years concerns have been raised about Rulemaking End stage kidney disease means the safety of all OSP, both solutions and C. Other Regulatory History Relevant to complete or near complete failure of the tablets, for bowel cleansing. This Rulemaking III. Safety Concerns About the Use of Oral kidneys to function. Most recently, FDA received a Sodium Phosphate Products for Bowel GFR is an abbreviation for glomerular petition requesting that FDA either Cleansing filtration rate; is a measure of kidney withdraw the marketing authorization of A. Summary of FDA’s Adverse Event function. GFR can be obtained by OSP for bowel cleansing or limit the Reporting System Data measuring creatinine clearance or by marketing of these products to B. Summary of the Available Published estimating creatinine clearance. The prescription only and require a ‘‘black Data creatinine clearance is measured by box’’ warning (Ref. 1). The petition C. Consensus Statement on Bowel using the values of urine creatinine presented the following arguments to Preparation Before Colonoscopy concentration, urine flow rate, and support these requests: D. FDA’s Tentative Conclusions on the plasma creatinine concentration, while • Safety of Nonprescription Sodium Trend data on adverse events Phosphate Oral Solutions for Bowel the estimated creatinine clearance is demonstrate an increase in the number Cleansing calculated by using a formula that uses of reports of acute renal failure and IV. FDA’s Tentative Conclusions on the measured serum creatinine. Creatinine nephrocalcinosis associated with the Safety and Effectiveness of Other Doses clearance is not a precise GFR use of OSP for bowel cleansing. of Sodium Phosphates Oral Solution for measurement, but rather an accepted • The available published data Bowel Cleansing surrogate for GFR. suggest that the problem is larger in V. Summary of Significant Changes From the Nephrocalcinosis means a condition scope than initially believed. 1985 Proposed Rule for OTC Laxative characterized by precipitation of • The occurrence of nephrocalcinosis Drug Products calcium phosphate in the tubules of the in individuals with no identifiable risk VI. Proposed Effective Date kidney resulting in kidney injury. factors renders screening insufficient. VII. Analysis of Impacts • A. Background NSAID is an abbreviation for There are equally effective and safer B. Need for the Proposed Rule nonsteroidal anti-inflammatory drug; alternative bowel preparation agents C. Impact of the Proposed Rule OTC and prescription drugs that relieve that are available. D. Benefits of the Proposed Rule pain and inflammation. The petition stated that new safety E. Alternatives OSP is an abbreviation for oral information warrants reconsideration of F. Impact on Small Businesses sodium phosphates, the combination of the risk/benefit ratio to the public of the VIII. Paperwork Reduction Act of 1995 dibasic sodium phosphate and continued OTC and prescription use of IX. Environmental Impact monobasic sodium phosphate salts in a X. Federalism OSP products for bowel cleansing under XI. References tablet or solution dosage form. their present labeling. PEG is an abbreviation for FDA concluded that the currently I. Glossary polyethylene glycol, a prescription drug available information was not sufficient As used in this document: used for bowel cleansing. to warrant the withdrawal of OSP ACE inhibitor means angiotension- II. Background products from the market. However, converting enzyme inhibitor; a FDA also concluded that the use of OSP prescription drug for hypertension. A. Purpose of the Rule for bowel cleansing poses a serious risk Acute phosphate nephropathy means Oral sodium phosphates (OSP) of adverse events in some patients and a type of nephrocalcinosis attributed to products are frequently recommended that current measures of mitigating the use of oral sodium phosphate by physicians for bowel cleansing prior these risks have been unsuccessful. products. to a colonoscopy and other medical Therefore, on December 11, 2008, FDA Acute kidney failure means sudden procedures. Both prescription tablet granted the petition’s request to limit inability of the kidney to remove wastes, dosage forms and OTC OSP solution the marketing of OSP products for concentrate urine, and conserve have been used for this purpose. This bowel cleansing to prescription only electrolytes. document addresses the use of OTC and to require a boxed warning in ARB is an abbreviation for OSP solutions for bowel cleansing. The product labeling (Ref. 2). We also angiotension receptor blocker, a customary dose of OTC OSP solution concluded that additional measures prescription drug for hypertension. used in medical practice for bowel were necessary to manage the potential

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risks associated with the use of be provided to health professionals in cleansing regimen in preparing the prescription OSP products for bowel separate labeling distributed by patient for surgery or for preparing the cleansing. Under new authority granted pharmaceutical sales representatives. colon for x-ray endoscopic by the Food and Drug Administration The proposed labeling would have examination.’’ Thus, this proposed rule Amendments Act of 2007, FDA stated provided certain information to would amend § 310.545 (21 CFR that it had notified the NDA holder of healthcare professionals about the use of 310.545) to include sodium phosphate prescription OSP products that it must sodium phosphate products for bowel salts, singly and in combination for develop a risk evaluation and mitigation cleansing use. In this document we are bowel cleansing use as described in strategy (REMS) that includes the proposing that the professional labeling § 334.80 of the 1985 TFM. development of a Medication Guide and for the use of sodium phosphates salts In addition, the safety issues raised by a communication strategy targeted at for bowel cleansing use be removed the prescription and professional use of healthcare providers who are likely to from the 1985 TFM because of our OSP for bowel cleansing has led FDA to prescribe or dispense OSP products safety concern with the bowel cleansing reconsider the appropriateness of bowel and/or perform followup assessments of use of OSP products. This proposed rule cleansing, as described in § 334.66, as patients following bowel cleansing. We does not address the proposed an OTC indication. FDA will address also determined that prospective professional labeling for bowel the status of bowel cleansing as an OTC clinical trials are necessary to assess the cleansing for other active ingredients indication in a future Federal Register risk of acute kidney injury in patients included in § 334.80. FDA intends to publication. using prescription OSP products for address the proposed professional B. Chronology of the Federal Register bowel cleansing, and to better define the labeling of these active ingredients in a Publications Addressing Professional risk factors that predispose patients to future Federal Register publication. Labeling for Sodium Phosphate Salts in such injury. This proposed rule is consistent with the OTC Laxative Drug Products Specifically, this document addresses the agency’s determination that OSP Rulemaking the proposed professional labeling for products indicated for bowel cleansing OTC sodium phosphate salts for bowel should be limited to prescription only. The current proposal is part of FDA’s cleansing described in § 334.80 of the In this document FDA also proposes to ongoing review of OTC drug products. 1985 TFM. Under the 1985 TFM, this classify, the individual sodium There are earlier Federal Register additional labeling would have been phosphate salts (i.e., dibasic sodium publications relevant to the use of OTC provided only to healthcare phosphate and monobasic sodium sodium phosphate salts for bowel professionals and not the general public, phosphate), as not GRAS (i.e., cleansing. A summary of relevant and the labeling would not have been nonmonograph) for the professional Federal Register publications is included as part of the OTC drug labeling indication proposed in the 1985 provided in table 1 of this document as product label. Professional labeling may TFM, i.e., ‘‘For use as part of a bowel follows:

TABLE 1—OTC LAXATIVE DRUG PRODUCTS RULEMAKING FOR MONOBASIC SODIUM PHOSPHATE AND DIBASIC SODIUM PHOSPHATE 1

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March 21, 1975 (40 FR 12902), advance notice Recommendations of the Advisory Review Panel on OTC Laxative, Antidiarrheal, Emetic, and of proposed rulemaking (ANPR) for OTC lax- Antiemetic Drug Products (Panel) ative drug products. 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 im- paired renal functions as hyperphosphatemia and hypocalcaemia may occur.’’ The Panel did not recommend that the sodium phosphates salts bear an indication for prepa- ration of the colon for x-ray and endoscopic examination. (50 FR 12902 at 12940 and 12942) January 15, 1985 (50 FR 2124), tentative final FDA adds a provision for OTC bowel cleansing systems in § 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 pre- paring 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) Amendment to Based on a number of deaths related to the OTC availability of a 240-milliliter (mL) container TFM for OTC laxative drug products. 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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TABLE 1—OTC LAXATIVE DRUG PRODUCTS RULEMAKING FOR MONOBASIC SODIUM PHOSPHATE AND DIBASIC SODIUM PHOSPHATE 1—Continued

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May 21, 1998 (63 FR 27836), final rule, pack- FDA determines that the continued OTC availability of a 240-mL container size of sodium age size limitation and warning and directions phosphates oral poses a serious safety concern and that it cannot wait for a laxative final statements for sodium phosphates oral solu- rule to address this concern. FDA publishes a final rule that limits the container sizes to not tions. 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 fol- lowing: • ‘‘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), amendment to In an amendment to the 1985 TFM, FDA proposes extensive additional labeling for the profes- TFM for OTC laxative drug products. sional use of oral and rectal sodium phosphate drug products that: • Warns healthcare professionals about the use of sodium phosphates products in the el- derly, in patients taking drugs that may affect electrolyte levels, or in patients with: Æ congestive heart failure Æ impaired renal function Æ heart disease Æ acute myocardial infarction Æ unstable angina Æ preexisting electrolyte disturbances (such as dehydration, or those secondary to the use of diuretics) • Advises monitoring electrolytes and giving sufficient fluid replacement to prevent dehydra- tion. • 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 phos- phate drug products that: • Warns about the use of rectal dosage forms of sodium phosphate products in children under 2 or in patients with Æ megacolon Æ imperforate colon Æ colostomy Æ rectal abnormalities Æ 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 phos- phate and 20.2 g monobasic sodium phosphate in a 24-hour period in the OTC or profes- sional labeling in the final monograph for OTC laxative drug products. December 7, 1998 (63 FR 67399) ...... Final rule; stay of compliance with the 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 67817), notice of FDA withdraws its proposed amendment of § 334.80(b)(2) of the 1985 TFM to add expanded withdrawal of TFM amendment of May 21, professional labeling for oral and rectal sodium phosphates drug products and states the in- 1998 (63 FR 27886). tent to further expand the professional labeling in a future proposed rule. November 29, 2004 (69 FR 69278) ...... Final rule to extend the sodium content 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 phos- phate’’ 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 recognized as safe and effective include six bowel cleansing systems This Rulemaking (GRASE) for OTC use as bowel cleansers (Refs. 3 and 4). In a letter dated October (50 FR 2124 at 2153). The proposed 26, 1989, FDA responded to the petition 1. Citizen Petition To Include Bowel combinations did not include sodium and found that two of the six requested Cleansing Systems Containing Sodium phosphate ingredients. In a petition kits could be GRASE for OTC use for Phosphates Oral Solution dated November 12, 1987, and a bowel cleansing (Ref. 5). Both kits In the 1985 TFM, FDA proposed that subsequent supplemental submission to include sodium phosphates oral certain combination bowel cleansing the petition, a manufacturer requested solution as a component. One kit systems could be considered generally that FDA amend the 1985 TFM to contains three laxatives for sequential

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

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III. Safety Concerns About the Use of with cardiac events had electrolyte inhibitor or ARB was noted in 11 cases, Oral Sodium Phosphate Products for abnormalities. However, the dose of diuretic use in 6 cases, NSAID use in 4 Bowel Cleansing sodium phosphates involved in most of cases; and 1 patient received a contrast these cases was well in excess of 59.4 dye. Five cases were reported to be life- A. Summary of FDA’s Adverse Event g. threatening and 10 resulted in Reporting System Data Since 2005, there have been an hospitalization. Of these 20 cases, As described previously, FDA has additional 46 reports of acute kidney 4 patients required dialysis for an previously made a number of attempts failure that have been associated with unspecified period of time and 1 patient to educate healthcare professionals and the use of OTC sodium phosphates oral died from complications of pneumonia. consumers about the risk of adverse solution for bowel cleansing. Twelve of Nine patients were reported to have effects on the kidneys that have been these cases were reported in a published kidney impairment that continued for at associated with the use of OSP products abstract (Ref. 30) with only limited least 2 to 4 weeks. The status of renal for bowel cleansing. In addition to information. The remaining 34 cases impairment is unknown for seven measures taken by FDA, in 2005 a major were reported in the AERS data base. Of patients.2 manufacturer of OTC sodium the AERS cases, one required a kidney phosphates oral solution products transplant, one was placed on a kidney B. Summary of the Available Published distributed updated professional transplant list, six required dialysis, and Data labeling containing detailed safety four cases had long term decreased In addition to the FDA AERS cases information and dosing instructions kidney function. More recently (January described previously, there are also (60 g of sodium phosphates (dibasic 2008), FDA received two reports of reports of acute kidney injury associated sodium phosphate and monobasic acute kidney injury associated with a with the use of sodium phosphate sodium phosphate salts) solution taken lower dose sodium phosphate oral products for bowel cleansing in the orally as two 45-mL doses 12 hours solution regimen, i.e., a 45-mL dose published literature. It is not clear from apart or approximately 50 g of sodium followed by 30-mL dose administered the reports whether these adverse events phosphates taken as a 45-mL dose 10 to 12 hours apart. Both of these cases were associated with the use of an OTC followed by a 30-mL dose 12 hours resulted in hospitalization. or prescription product. later) (Ref. 29). Despite these measures An OSP in a tablet dosage form has The 21 cases of acute phosphate and the development of products with been approved for prescription use as a nephropathy cited in the May 2006 a reduced sodium phosphate dose, bowel cleanser since 2000. The sodium Health Alert were identified by FDA’s Adverse Event Reporting System phosphate dose of this product is 60 g. Markowitz et al. (Ref. 31) from kidney (AERS) continues to receive reports of In 2006, FDA approved a sodium biopsy archives at the Columbia acute kidney injury that have been phosphate tablet with a lower sodium University Renal Pathology Laboratory. associated with the customary dose of phosphate dose (48 g) for the same From 2000 to 2004, the laboratory these products for bowel cleansing. indication. There have also been a processed a total of 7,349 native renal To date, AERS has received over 100 number of reports of acute kidney injury biopsies (transplanted kidneys were serious adverse event reports associated associated with the use of both of these excluded), from which 31 cases were with the use of prescription and products. retrieved with findings of kidney tubule nonprescription OSP products for bowel Since 2001, FDA has received 16 injury and abundant calcium deposits. cleansing at the customary dose. Acute cases of acute kidney injury that were Of these 31 cases, 21 had normal renal injury associated with this use of likely associated with the use of the 60- calcium levels and met the criteria for OSP for bowel cleansing has led to g prescription product. Ten of these acute phosphate nephropathy and had a kidney transplant, dialysis, long term cases required hospitalization, and at recent colonoscopy preceded by OSP renal failure and, in rare instances, least two required dialysis. Direct use. The incidence of acute phosphate death. The majority of these cases evidence of calcium phosphate nephropathy reported in this study was occurred in patients with additional risk precipitation in kidney tubules was 0.29 percent (21 of 7,349). factors for kidney injury as identified in obtained by biopsy in one case. There Clinical followups were available for the May 2006 Health Alert (see section were also 10 cases of seizure. In at least all 21 cases (mean 16.7 months). All 21 II.C.5 of this document). There were nine of these cases there was no cases had increased serum creatinine, cases, however, that occurred in previous history of seizure, and seizures an indication of decreased kidney patients without additional risk factors. began between 2 to 16 hours after use function, (mean 3.9 mg/deciliter (mg/ From 1969 to 2005, FDA received 33 of OSP. In all 10 seizure cases, the dL)) at a median of 1 month after reports of acute kidney injury reported patient had low blood sodium levels, colonoscopy. Four cases (19 percent) to be associated with the use of OTC and required hospitalization. Five of the progressed to end stage kidney failure 9 sodium phosphates oral solution for cases of renal failure and two of the to 18 months (mean 13.8 months) after bowel cleansing. Among the 33 reports, cases of seizure did not follow labeled colonoscopy and required dialysis. 4 cases developed end-stage kidney directions for use, which may have These four patients required kidney disease with one case requiring a kidney contributed to the adverse event. replacement therapy, and one of the transplant. At least 22 of the 33 cases Since approval of the 48-mg dosage four underwent successful kidney developed chronic kidney failure, with form of sodium phosphate tablets in transplant. Although 16 of the at least 9 cases requiring hospitalization 2006, 20 unique cases of kidney injury remaining 17 cases (94 percent) had a and 7 requiring dialysis. Only 5 of the associated with the use of this lower subsequent improvement in kidney 33 cases of acute kidney injury involved dose product have been reported to function, none returned to baseline a dose of sodium phosphate in excess of AERS through September 12, 2008. The creatinine levels and were left with 59.4 g.1 In addition to the cases of acute onset of the kidney injury occurred from some degree of renal impairment. kidney injury, there were reports of 11 several hours to 21 days after taking the The demographic and clinical fatalities, 2 cases of seizure, and 12 product. Three of these patients had a findings for these 21 cases suggest that serious cardiac events. Most of the cases kidney biopsy, the results of which age and the co-administration of agents revealed acute phosphate nephropathy. 1 Outcomes are not mutually exclusive. The concomitant use of an ACE 2 Outcomes are not mutually exclusive.

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

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

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A total of 88 patients were identified C. Consensus Statement on Bowel D. FDA’s Tentative Conclusions on the as having renal impairment after Preparation Before Colonoscopy Safety of Nonprescription Sodium colonoscopy. The proportion of patients Phosphate Oral Solutions for Bowel with renal impairment after In 2006, a Joint Task Force from the Cleansing colonoscopy was similar between OSP American Society of Colon and Rectal Surgeons (ASCRS), the American FDA has tentatively concluded that users (79/2083 (3.8 percent)) and PEG the customary dose of OTC sodium users (9/269 (3.3 percent)). Of these 88 Society for Gastrointestinal Endoscopy (ASGE), and the Society of American phosphate salts for bowel cleansing (i.e., cases, 50 patients had a GFR decrease of two 45-mL doses taken 12 hours apart 20 mL/min, and 13 had at least a Gastrointestinal and Endoscopic Surgeons (SAGES) issued a consensus or a 45-mL dose followed by a 30-mL twofold increase in creatinine after dose of sodium phosphates oral solution colonoscopy. In 21 out of those 88 cases, statement on bowel preparation before colonoscopy (Ref. 40). The task force 10 to 12 hours later) in an OTC setting GFR remained < 60 mL/min 6 months performed a critical scientific review of based on professional labeling in an after colonoscopy, and out of these 17 the available data, which included 21 OTC monograph poses an unacceptable had used OSP and 4 had used PEG. The randomized, controlled trials in the risk of serious adverse events. Some relative risk (RR) estimate for renal published literature. The scope of the patients have experienced sudden and impairment comparing OSP and PEG task group consensus statement severe acute kidney failure which may was 1.13 (95 percent confidence interval included not only the customary dose of require kidney dialysis, while others 0.58–2.23) without adjustment, and the OSP but also other treatment modalities have had a less serious course that Odds Ratio after multivariate for bowel preparation, including PEG. resolves with minimal intervention. The adjustment was 1.14 (0.55–2.39). Both oral solutions and the tablet outcome has varied from complete Significant risk factors were those formulations of OSP were assessed. recovery to, in rare instances, death. identified by earlier studies and include Some patients may have residual kidney age greater than or equal to 65, African In their consensus statement the Task damage and may never return to the American race, low baseline GFR, Force acknowledges the risks associated kidney function present prior to OSP hypertension and use of ACE inhibitors, with the customary dose of OSP for use. ARBs, or thiazide diuretics. The authors bowel cleansing. The Task Force drew Some of the retrospective studies that of the study concluded that in patients the following conclusions based on its have reviewed the serum creatinine of without preexisting kidney disease, the evaluation of the data: large numbers of patients who risk of kidney impairment after 1. The use of OSP for bowel underwent bowel preparation for colonoscopy appears to be similar preparation prior to a colonoscopy is colonoscopy at the customary OSP between OSP and PEG users. associated with abnormalities in serum doses suggest that the percent of cases It is difficult to make definitive electrolytes and altered extracellular leading to serious injury with symptoms conclusions from this study for the fluid volume, which can cause is relatively rare. However, there is no following reasons: significant losses of both fluid and accurate estimate of the incidence of electrolytes in the stool, resulting in acute kidney injury in patients receiving 1. A significantly greater proportion of volume contraction and dehydration. these doses of OSP for bowel cleansing. OSP users who underwent colonoscopy 2. Rarely adverse events such as Some studies have identified were excluded from the study, which nephrocalcinosis with acute kidney populations who appear to be at risk, may introduce a potential selection bias. failure have occurred after use of OSP. but data from prospective studies are 2. There is a wide range of time 3. OSP use has been shown to cause needed to better define the risk of acute between measurements of serum elevated blood urea nitrogen levels, kidney injury in patients using OSP at creatinine. Although the authors decreased exercise capacity, increased the current doses as preparation for claimed that adjustment for differences plasma osmolality, hypocalcemia, and colonoscopy and to determine the risk in the latency time from colonoscopy to significant hyponatremia and seizures. factors that may predispose patients to creatinine determination did not alter such injury. the risk estimates, analysis of such data 4. Although usually asymptomatic, The study by Hurst also raises was not provided. hyperphosphatemia is seen in as many questions about the possible effects of as 40 percent of healthy patients 3. PEG users tended to have a higher small changes in serum creatinine that completing OSP preparations, and may occur after OSP use at the prevalence of co-morbid conditions hypokalemia developed in as many as (e.g., congestive heart failure, liver customary doses for bowel cleansing 20 percent of patients using OSP (Ref. 34). This is an important question cirrhosis) or used agents that potentially preparations. impair kidney perfusion. that needs to be addressed. There are The Task Force advised physicians to about 14 million screening 4. Two different criteria were used for select a preparation for each patient colonoscopies per year in the United identification of patients with renal based on the safety profile of the agent States., for which an estimated 50 impairment post colonoscopy. and the overall health of the patient, percent will use OSP for bowel There are limitations in the design of their comorbid conditions and currently cleansing (Ref. 31). Given the magnitude all of the five studies discussed prescribed medications. They further of the exposure, the possibility of low previously, such as the lack of a advised that in certain circumstances grade declines in GFR after exposure to consistent definition of acute kidney such as bowel preparation in children, OSP is troubling when one considers injury and the exclusion of patients the elderly, patients with renal that many patients undergo with baseline serum creatinine values insufficiency, and those with colonoscopies more than once in their above a threshold value. As a hypertension taking an ACE inhibitor or lifetime and the damage that occurs consequence, no definitive conclusions an ARB, it may be advisable to adhere with every exposure could be can be drawn from these studies, and to PEG-based solutions because of the cumulative for some individuals. Other additional studies are needed to further risk of occult physiologic disturbances studies have not supported the findings assess subclinical changes in kidney that may contraindicate the use of of Hurst. Thus, it is important that this function. sodium phosphates regimens. issue be addressed with clinical trials

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using more exact measurements of document that the professional labeling solution taken 10 to 12 hours apart (Ref. glomerular filtration rate. For these for bowel cleansing use be removed 14). However, the available data raise reasons, FDA has required the NDA from the tentative final monograph serious concerns about the safety of this holder of prescription OSP products to because of our safety concern with the regimen. conduct prospective, randomized, bowel cleansing use of sodium There are some data that suggest a active-controlled clinical trials to phosphate products. lower sodium phosphate dose may be determine the absolute and relative risk We also believe that the safe use of similar in effectiveness to the regimen of kidney injury (including acute OSP as presently used for bowel currently in use. An unpublished study phosphate nephropathy) following the cleansing requires the continuing comparing the effectiveness of sodium use of these products. involvement of a doctor to monitor its phosphates oral solution at two dose Further, because of continuing reports effects on kidney function. Section levels, the standard 2 x 45-mL dose of acute kidney injury associated with 503(b)(1) of the FD&C Act establishes (60 g sodium phosphate) and a reduced the prescription and customary dose of the standards under which the 2 x 30-mL dose (37 g sodium OTC OSP products for bowel cleansing, marketing of a drug must be limited to phosphate), with PEG solution was despite repeated educational efforts by prescription. Among these is the need included in a citizen petition from a FDA and the detailed professional for collateral measures for the safe use manufacturer of sodium phosphate labeling provided by a drug of the product and the need for the laxative products (Ref. 18). The study, manufacturer for these products, we involvement of a licensed practitioner to PS–9902, was a randomized, single- have tentatively concluded that OSP for ensure the safe use of the product. For blind, parallel group design. The two bowel cleansing at the currently used the reasons already given, the customary regimens were administered as divided doses poses a serious risk of adverse dose of OSP solution for bowel doses 10 to 12 hours apart. A total of events in some patients. Therefore, cleansing meets the statutory definition 238 subjects were randomized to one of additional measures are needed to of a prescription product. Thus, in this the three treatments. Seventy-four manage the risk posed by this use of document FDA proposes to classify OTC subjects took the 2 x 45-mL dose, and OSP products for bowel cleansing to sodium phosphate salts, singly or in 75 subjects took the 2 x 30 mL dose. assure that the benefits outweigh the combination with each other, as not There were 73 subjects who took PEG. potential risks. The need for these GRAS (i.e., nonmonograph) for the The study excluded all patients with additional measures precludes the professional labeling indication current labeling contraindications to continued use of the current regimen of proposed in the 1985 TFM, i.e., ‘‘For use OSP use and all patients for whom use sodium phosphates oral solution for as part of a bowel cleansing regimen in is allowed with caution. bowel cleansing under the professional preparing the patient for surgery or for The manufacturer’s evaluation of labeling of an OTC monograph. preparing the colon for x-ray endoscopic physicians’ assessments of bowel Under the current professional examination.’’ This proposed rule would preparation indicated no statistically labeling provisions of the 1985 TFM amend § 310.545 to include sodium significant differences between the 2 x published on January 15, 1985 (50 FR phosphate salts for bowel cleansing use, 30-mL sodium phosphates oral solution 2124), consumers rely on their as described in § 334.80 of the 1985 group and the PEG group for any of the healthcare provider to provide TFM, as nonmonograph. effectiveness endpoints: Residual stool, information on the safe use of the Screening colonoscopy can lead to the stool consistency, and bowel wall sodium phosphates oral solution for early detection of colon cancer and visualization parameters. Bowel bowel cleansing. This approach has not polyps, which, if not removed, can cleansing with the two 45-mL doses was been sufficient to manage the risk that progress to cancer. Early detection of found to be superior to the lower dose has been associated with the customary colon cancer can result in more effective OSP regimen and PEG. The observed dose of OTC sodium phosphates oral treatment and a survival advantage. electrolyte changes and side effects were solution for bowel cleansing. We believe Inadequate preparation for colonoscopy milder with the two 30-mL doses of OSP that consumers need to have detailed can lead to missed lesions. OSP compared to the two 45-mL dose. information in the form of patient products have been shown to be Elevation in serum sodium was the only labeling and information from a effective in cleansing the colon, thereby significant electrolyte change between physician regarding the safe use of the allowing better visualization of cancers the OSP groups. Four patients on the product. Risk information in patient and polyps. FDA believes it is important two 45-mL dose regimen had post-prep labeling could affect patients’ decisions to have multiple options available for sodium levels that exceeded the upper to use these products, and thus help bowel cleansing because no single limit of normal but remained below 150 prevent serious adverse effects. This product is tolerated by all individuals. millimole/Liter. kind of patient labeling (see 21 CFR It is important, however, to make sure While the results of this study are 201.57 and 21 CFR part 208) cannot be that the risk for serious injury is very worth noting, they are not sufficient to accomplished with professional labeling low and the appropriate populations are demonstrate the safety and effectiveness found in an OTC monograph. identified who can use these products of the reduced phosphate regimen. It is Professional labeling is labeling safely. noteworthy that 32 percent (23/73) of provided only to healthcare the PEG subjects reported that they did professionals who direct patients to use IV. FDA’s Tentative Conclusions on the not complete the treatment regimen. OTC products in ways that differ from Safety and Effectiveness of Other Doses This finding may have reduced the the consumer labeling for these of Sodium Phosphates Oral Solution for efficacy found in the PEG group, thereby products. Manufacturers marketing OTC Bowel Cleansing minimizing treatment effect differences products under the 1985 TFM cannot FDA has previously acknowledged between PEG and the low dose provide consumers with labeling the effectiveness of the bowel cleansing phosphate regimen. There were also information on the OTC package related regimen that is currently the standard of irregularities in randomization. Ten to those indications or uses that are not practice for OTC sodium phosphates patients were excluded following part of the drug facts labeling allowed oral solution, i.e., 60-g sodium randomization, because they were under the 1985 TFM. For all of these phosphate administered in two 45-mL randomized before all inclusion criteria reasons, we are proposing in this doses of sodium phosphates oral were verified. In addition, at one study

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site, six patients were randomized out of VII. Analysis of Impacts drug products in preparation for order and did not receive the treatments FDA has examined the impacts of the colonoscopy and x-ray before surgery. assigned by the randomization protocol. proposed rule under Executive Order A. Background Thus, the study results can not be 12866, the Regulatory Flexibility Act (5 FDA has taken a number of measures considered a conclusive demonstration U.S.C. 601–612), and the Unfunded of the effectiveness of these products. In to mitigate the risk of serious adverse Mandates Reform Act of 1995 (Pub. L. events associated with the use of OSP addition, while the electrolyte changes 104–4). Executive Order 12866 directs and side effects were milder with the products in preparation for colonoscopy agencies to assess all costs and benefits and x-ray endoscopic examination. As two 30-mL doses of sodium phosphates of available regulatory alternatives and, oral solution, the number of subjects discussed in the preamble, FDA has when regulation is necessary, to select limited the acceptable container sizes exposed to the proposed lower dose regulatory approaches that maximize regimen (79 subjects) is too small to that can be marketed and added net benefits (including potential warnings and direction statements to allow any conclusions about the safety economic, environmental, public health of the lower dose regimen. OTC sodium phosphates solutions and safety, and other advantages; marketed for laxative and to healthcare V. Summary of Significant Changes distributive impacts; and equity). The professionals for bowel cleansing use. From the 1985 Proposed Rule for OTC agency believes that this proposed rule Separate from this proposed rule, the Laxative Drug Products is not a significant regulatory action as agency has also made several attempts defined by the Executive order. 1. FDA is classifying sodium to educate and alert both healthcare The Regulatory Flexibility Act professionals and consumers about phosphate salts described in § 334.16(d), requires agencies to analyze regulatory (e) and (f), as nonmonograph and potential risks associated with options that would minimize any customary dose of OSP products for removing them as acceptable active significant impact of a rule on small ingredients for the use as a bowel bowel cleansing. Despite these entities. Because this proposed rule only measures, FDA’s AERS has continued to cleansing agent described in affects labeling provided to healthcare § 334.80(a)(2). receive reports of acute kidney injury professionals for the indication of bowel that have been associated with the 2. FDA is removing the warning in cleansing and does not affect the customary dose of OSP products for § 334.80(b)(2) for sodium phosphate marketing of sodium phosphates oral bowel cleansing. salts. The warning will be revised and solution for consumer use as a laxative For this reason, on December 12, included in a proposed rule to be for the relief of occasional constipation, 2008, FDA took steps to limit the published at a future date. the agency proposes to certify that the marketing of OSP products for bowel VI. Proposed Effective Date final rule will not have a significant cleansing to prescription only and to economic impact on a substantial increase the prominence of risk The existing evidence is inadequate to number of small entities. information by requiring a boxed establish the safety of OTC sodium Section 202(a) of the Unfunded warning on prescription OSP products phosphate salts (dibasic sodium Mandates Reform Act of 1995 requires (Ref. 1). In addition, the continued phosphate, monobasic phosphate and that agencies prepare a written marketing of prescription OSP products dibasic sodium phosphate/monobasic statement, which includes an will require the development of a risk sodium phosphate (sodium phosphates) assessment of anticipated costs and evaluation and mitigation strategy that solution) for professional use as a bowel benefits, before proposing ‘‘any rule that includes the development of a cleansing preparation prior to surgery or includes any Federal mandate that may Medication Guide and a communication endoscopic examination. Accordingly, result in the expenditure by State, local, strategy targeted at healthcare providers sodium phosphate salts cannot be and Tribal governments, in the who are likely to prescribe OSP considered GRAS for OTC use for bowel aggregate, or by the private sector, of products. FDA has also instructed the cleansing. $100,000,000 or more (adjusted holders of NDAs for OSP products to If this proposal becomes a final rule, annually for inflation) in any one year.’’ conduct prospective clinical trials to the conditions under which drug The current threshold after adjustment assess the risk of acute kidney injury in products subject to this rule are not for inflation is $135 million, using the patients using sodium phosphate GRASE and are misbranded will be most current (2009) Implicit Price products for bowel cleansing and to effective 30 days after the date of the Deflator for the Gross Domestic Product. better define the risk factors that final rule’s publication in the Federal FDA does not expect this proposed rule predispose patients to such injury. FDA Register. On or after that date, any OTC to result in any 1-year expenditure that has taken these steps in an attempt to laxative products containing dibasic would meet or exceed this amount. increase the level of risk communication sodium phosphate or monobasic The purpose of this proposed rule is for these products and thereby reduce phosphate and dibasic sodium to remove the professional labeling the incidence of adverse events that has phosphate/monobasic sodium relating to the use of sodium phosphates been associated with these products. phosphate (sodium phosphates) oral solution laxatives for bowel marketed for bowel cleansing will be cleansing in the 1985 TFM (50 FR 2124 B. Need for the Proposed Rule misbranded and will require an at 2157). Professional labeling is This proposed rule is consistent with approved NDA for bowel cleansing use information directed to health the Agency’s determination that the and marketing. Any OTC drug product professionals who prescribe, administer, customary dose of OSP products for subject to the final rule that is or dispense medications, and may not bowel cleansing (i.e., approximately repackaged or relabeled after the be included in labeling directed to the 60 g of sodium phosphates taken as two effective date of the final rule must be consumer. This proposed rule amends 45-mL doses 12 hours apart or in compliance with the final rule, § 334.80 to remove the bowel cleansing approximately 50 g of sodium regardless of the date the product was indication for sodium phosphates oral phosphates taken as a 45-mL dose initially introduced or initially solution laxatives based on concerns followed by a 30-mL dose 12 hours delivered for introduction into interstate about serious adverse reactions later) poses a serious risk to some commerce. associated with the use of these OTC individuals and that the marketing of

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these products for bowel cleansing indication, these manufacturers will resulting from acute renal failure should be limited to prescription only. incur the cost of relabeling to remove without dialysis has been estimated at In this document FDA proposes to the bowel cleansing use from their $22,251 (51 FR 77314 at 77344, classify OTC sodium phosphate salts, labels. These costs would be incurred December 26, 2006). Recent analyses singly or in combination with each without this rule, because professional have reported Medicare payments for a other, as not GRAS (i.e., nonmonograph) uses of OTC drugs are not properly year’s treatment of a dialysis patient of for bowel cleansing. Furthermore, FDA included in labeling directed to about $67,000. Employer group health is proposing to remove professional consumers. insurance costs are much higher at labeling for bowel cleansing use from We analyzed proprietary data from $180,000 per year (Ref. 41). the monograph. Manufacturers of OTC SDI Health on the total number of retail Estimates of the cost of kidney OSP laxative products would no longer prescriptions dispensed for bowel transplants also vary. Associated be able to promote the use of these preparation products from March 2004 medical costs for transplants average products to healthcare professionals for through February 2009. We included about $102,000 in the year of the bowel cleansing use. Consequently, the PEG products and OSP products that are transplant (Ref. 42). The mean cost of marketing of sodium phosphates oral considered alternatives to the OTC OSP hospitalization for a kidney transplant solution marketed under an OTC drug products for bowel cleansing. The procedure was $128,000 in 2006 (Ref. monograph would be limited to laxative number of prescriptions for PEG 43). In addition, patients with kidney use at a lower sodium phosphates dose products has grown significantly over transplants require immunosuppressive to relieve occasional constipation. this time period, whereas the number of drugs for years after their transplant. OSP products remained relatively We believe, based on the available C. Impact of the Proposed Rule constant over most of this period and data, that sodium phosphates solution Executive Order 12866 and OMB began to decline in late 2008. The marketed under an OTC drug Circular A–4 direct agencies to consider average annual growth rate for all monograph for bowel cleansing may be and provide a description of any prescription bowel preparation products a significant cause of severe adverse important distributional effects that was 17 percent from 2006 to 2008. From events. However, we note that there is might be attributed to a regulation, 2006 through the third quarter of 2008, uncertainty about the baseline risk of where applicable. To the extent that the monthly share of sodium phosphate serious adverse events associated with OTC OSP products for bowel prescriptions dispensed for bowel customary dose of OSP products (for preparation remain on the market, this preparation was about 13 to 15 percent both OTC and prescription uses). It is rule would shift those sales to of total prescriptions, but declined to a not possible to predict a specific level prescription products only. Any such monthly low of 7 percent by February of reduction in the incidence of these shift in sales represents a transfer 2009. This apparent decline in serious adverse events that might be payment between manufacturers within dispensed prescription sodium attributable to limiting OSP products for the industry and is not a social cost of phosphate products may be a market bowel cleansing use to prescription drug this rule. The agency believes that most response to recent agency actions, use. Moreover, to the extent that OSP of this transfer has already occurred including the boxed warning products have been voluntarily through voluntary withdrawal of OTC requirement, that are separate from this withdrawn from the market, this rule products by their manufacturers. rule. However, it is too soon to would not have an impact on the An informal in-store review of several determine market changes. Nonetheless, incidence of these serious adverse national drug and mass merchandise the data on the number of prescriptions events. stores found that there were no OTC dispensed suggest that prior agency E. Alternatives liquid OSP products on those store actions may have had a dampening shelves. Pharmacists indicated that OSP market effect on the use of OSP The agency considered but rejected liquid products were removed from the products for bowel preparation. several alternatives: (1) Requiring shelves in response to information from additional (OTC or professional) FDA. Therefore, the agency believes that D. Benefits of the Proposed Rule labeling that describes potential adverse any shift in sales from OTC to Section III.A of this document effects, the subpopulations at greatest prescription products for bowel presents data on the reports of serious risk, and detailed directions about cleansing that would have been adverse events associated with hydration, (2) a longer implementation attributed to this rule most likely has prescription and OTC products period for this rule if finalized, and already occurred. containing sodium phosphates for (3) product withdrawal, including According to proprietary data from bowel cleansing. More than 100 adverse prescription use. We do not believe that A.C. Nielsen, annual retail sales for OSP events have been reported that are the first two alternatives to the proposed products totaled about $30 million in associated with the customary dose of regulation would be adequate to provide 2006. The vast majority of these sales OSP products as presented in section III. for the safe use of OTC sodium are attributed to one manufacturer. That A of this document. Although these phosphates oral solution for bowel manufacturer has already voluntarily serious events are rare, the public health cleansing (e.g., preparation for removed its OSP laxative products from consequences can be substantial. Acute colonoscopy). Various attempts at the shelves. We believe that other phosphate nephropathy that has been conveying the risk associated with OTC suppliers have similarly removed their associated with the customary dose of sodium phosphates oral solution products. The agency requests specific OSP for bowel cleansing can result in products, including detailed comments on this assumption. permanent impairment of kidney professional labeling describing To the extent that any OSP products function that ultimately may require potential adverse events and at risk for laxative use might remain on the chronic dialysis or kidney transplant, populations (Ref. 29) by a manufacturer market, there would be no relabeling or and may result in long term renal failure of an OTC sodium phosphates oral reformulation costs attributed to this and, in rare instances, death. solution product have not been rule. If, however, manufacturers have The economic consequences of this successful in reducing the number of chosen to improperly label their OSP severity of renal impairment are serious adverse events attributed to products with a bowel cleansing significant. The cost of hospitalization these products. The agency also

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considered but rejected a longer initial regulatory flexibility analysis as Management (HFA–305), 5630 Fishers implementation period for this required under the Regulatory Lane, rm. 1061, Rockville, MD 20852, proposed rule if finalized, because of Flexibility Act. Finally, this analysis under Docket No. FDA–1978–N–0021 the overriding safety considerations. We shows that the Unfunded Mandates (formerly Docket No. 78N–036L) and rejected the third alternative, to Reform Act does not apply to this may be seen by interested persons withdraw the product, because OSP has proposed rule because it would not between 9 a.m. and 4 p.m., Monday been demonstrated to be effective for result in an expenditure in any 1 year through Friday. bowel cleansing, and we believe that it by State, local, and Tribal governments 1. Document Id. FDA–2007–P–0345– is important to continue to have in the aggregate, or by the private sector 0003, Federal Dockets Management multiple options available for bowel of $135 million. System. cleansing because no single product is FDA invites public comment 2. Document Id. FDA–2007–P–0345– tolerated by all individuals. regarding any significant economic 0005, Federal Dockets Management System. F. Impact on Small Businesses impact that this proposal would have on affected manufacturers of sodium 3. Comment No. CP8, Docket 1978N– The Small Business Administration phosphates oral solutions. Comments 036L, Division of Dockets Management. (SBA) defines an entity as small in the regarding the impact of this proposal 4. Comment No. SUP5, Docket No. pharmaceutical manufacturing industry should be accompanied by appropriate 1978N–036L, Division of Dockets if the business has fewer than 750 documentation. FDA will evaluate any Management. employees. Over 90 percent of comments and supporting data that are 5. Comment No. LET41, Docket No. manufacturers in the OTC received and will reassess the economic 1978N–036L, Division of Dockets pharmaceutical industry are classified impact of this rulemaking in the Management. as small. To the extent that there preamble to any final rule. 6. Document Id. FDA–1978–N–0021– continue to be manufacturers of OSP 0032–0036, Federal Dockets products for bowel preparation that VIII. Paperwork Reduction Act of 1995 Management System. remain on the market, those sales would This proposed rule contains no 7. Comment No. CP14, Docket No. be shifted to prescription products. This collections of information. Therefore, 1978N–036L, Division of Dockets is a transfer payment and not a social clearance by the Office of Management Management. cost of this rule. The agency believes and Budget under the Paperwork 8. Comment No. SUP8, Docket No. that most of this impact has already Reduction Act of 1995 is not required. 1978N–036L, Division of Dockets occurred with manufacturers Management. voluntarily withdrawing products from IX. Environmental Impact 9. Comment No. AMD10, Docket No. the market prior to this rule. FDA has determined under 21 CFR 1978N–036L, Division of Dockets We estimate that there are about 10 25.31(a) that this action is of a type that Management. manufacturers that could be affected by does not individually or cumulatively 10. Comment No. LET71, Docket No. this proposed rule and that all of them have a significant effect on the human 1978N–036L, Division of Dockets are small businesses. The economic environment. Therefore, neither an Management. impact on any remaining individual environmental assessment nor an 11. Comment No. SUP11, Docket No. firms will vary based on the amount of environmental impact statement is 1978N–036L, Division of Dockets lost production and lost sales revenue required. Management. that is derived from sales of the OSP 12. Comment No. SUP10, Docket No. products for bowel cleansing. Without X. Federalism 1978N–036L, Division of Dockets knowing the volume of OTC OSP sales We have analyzed this proposed rule Management. that can be attributed to this use, it is in accordance with the principles set 13. Comment No. C146, Docket No. difficult to estimate the impact of this forth in Executive Order 13132. Section 1978N–036L, Division of Dockets proposed rule on small business 4(a) of the Executive order requires Management. entities. As noted above, a major agencies to ‘‘construe * * * a Federal 14. Comment No. LET109, Docket No. manufacturer of OTC OSP labeled for statute to preempt State law only where 1978N–036L, Division of Dockets professional use for bowel cleansing has the statute contains an express Management. already voluntarily withdrawn its bowel preemption provision or there is some 15. Comment No. PDN4, Docket No. cleansing products from the market. The other clear evidence that the Congress 1978N–036L, Division of Dockets remaining suppliers may have done the intended preemption of State law, or Management. same. where the exercise of State authority 16. Comment No. CP1, Docket No. Given the small number of conflicts with the exercise of Federal 00P–1472, Division of Dockets manufacturers of these products, we authority under the Federal statute.’’ Management. believe that it is unlikely that this The sole statutory provision giving 17. Comment No. PDN1, Docket No. proposed rule will have a significant preemptive effect to the proposed rule is 00P–1472, Division of Dockets economic impact on a substantial section 751 of the FD&C Act (21 U.S.C. Management. number of small entities. Nonetheless, 379r). 18. Comment No. CP28, Docket No. the agency requests detailed comments We believe that the preemptive effect 1978N–036L, Division of Dockets on small businesses impacts. The of this proposed rule, if finalized, would Management. proposed rule will not require any new be consistent with Executive Order 19. Comment No. LET204, Docket No. recordkeeping and no additional 13132. Through the publication of this 1978N–036L, Division of Dockets professional skills are needed. proposed rule, we are providing notice Management. This analysis shows that this and an opportunity for State and local 20. Document Id. FDA–1978N–0021– proposed rule is not economically officials to comment on this rulemaking. 0031, Federal Dockets Management significant under Executive Order System. 12866. Thus, this economic analysis, XI. References 21. Comment No. C207, Docket No. together with other relevant sections of The following references are on 1978N–036L, Division of Dockets this document, serves as the agency’s display in the Division of Dockets Management.

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22. Comment No. C208, Docket No. Journal of the American Society of authority delegated to the Commissioner 1978N–036L, Division of Dockets Nephrology, 18: 199–3205, 2007. of Food and Drugs, it is proposed that Management. 36. Abaskharoun, R., W. Depew, and 21 CFR parts 310 and 334 (as proposed 23. Comment No. SUP18, Docket No. S. Vanner, ‘‘Changes in Renal Function in the Federal Register of January 15, 1978N–036L, Division of Dockets Following Administration of Oral 1985 (50 FR 2124)), October 1, 1986 (51 Management. Sodium Phosphate or Polyethylene FR 35136), September 2, 1993 (58 FR 24. FDA Science Background Paper: Glycol for Colon Cleansing Before 46589), March 31, 1994 (59 FR 15139), ‘‘Safety of Sodium Phosphates Oral Colonoscopy,’’ Canadian Journal of September 2, 1997 (62 FR 46223), May Solution’’ September 17, 2001 in OTC Gastroenterology, April: 21(4):227–31, 21, 1998 (63 FR 27886), June 19, 1998 Volume 09OSPPR. 2007. (63 FR 33592), March 24, 2004 (69 FR 25. FDA Science Background Paper: 37. Khurana A., L. McLean, S. 13765), November 29, 2004 (69 FR ‘‘Acute Phosphate Nephropathy and Atkinson, and C. J. Foulks, ‘‘The Effect 69278), be amended as follows: Renal Failure Associated with the Use of Oral Sodium Phosphate Drug of Oral Sodium Phosphate Bowel Products on Renal Function in Adults PART 310—NEW DRUGS Cleansing Products,’’ May 2006 in OTC Undergoing Bowel Endoscopy,’’ 1. The authority citation for 21 CFR Volume 09OSPPR. Archives of Internal Medicine, March part 310 continues to read as follows: 26. FDA Information for Healthcare 24:168(6):593–7, 2008. Authority: 21 U.S.C. 321, 331, 351, 352, Providers: Oral Sodium Phosphate 38. Levey, A. S., T. Greene, J. Kusek, and G. Beck, ‘‘A Simplified Equation to 353, 355, 360b–360f, 360j, 361(a), 371, 374, Products for Bowel Cleansing, May 2006 375, 379e; 42 U.S.C. 216, 241, 242(a), 262, in OTC volume 09OSPPR. Predict Glomerular Filtration Rate from 263b–263n. 27. FDA Alert: Oral Sodium Serum Creatinine (abstract), Journal of 2. Section 310.545 is amended by Phosphate (OSP) Products for Bowel the American Society of Nephrology, 11: redesignating paragraph (a)(12)(ii) as Cleansing (marketed as Visicol and p.155A, 2000. paragraph (a)(12)(ii)(A), by adding OsmoPrep, and oral sodium phosphate 39. Russman, S. et al., ‘‘Risk of paragraph (a)(12)(ii)(B), by revising products available without a Impaired Renal Function After paragraph (d) introductory text and prescription), December 11, 2008 in Colonoscopy: A Cohort Study in paragraph (d)(1), and by adding OTC volume 09OSPPR. Patients Receiving Either Oral Sodium paragraph (d)(53) to read as follows: 28. FDA Information for Healthcare Phosphate or Polyethylene Glycol,’’ Professionals: Oral Sodium Phosphate American Journal of Gastroenterology, § 310.545 Drug products containing (OSP) Products for Bowel Cleansing 102:2655–2663, 2007. certain active ingredients offered over-the- (marketed as Visicol and OsmoPrep, and 40. Wexner, S.D. et al., ‘‘A Consensus counter (OTC) for certain uses. oral sodium phosphate products Document on Bowel Preparation Before (a) * * * available without a prescription), Colonoscopy,’’ prepared by a task force (12) * * * December 11, 2008, in OTC volume from the American Society of Colon and (ii) * * * 09OSPPR. Rectal Surgeons (ASCRS), the American (B) Saline laxatives—Approved as of 29. Professional Labeling for Fleets Society for Gastrointestinal Endoscopy [INSERT DATE 30 DAYS AFTER DATE Phosphasoda in OTC volume 09OSPPR. (ASGE), and the Society of American OF PUBLICATION OF THE FINAL 30. Khurana, A. et al., ‘‘Acute Gastrointestinal and Endoscopic RULE IN THE FEDERAL REGISTER]. Phosphate Nephropathy,’’ Journal of the Surgeons (SAGES), Gastrointestinal Dibasic sodium phosphate, monobasic American Society of Nephrology, 17: Endoscopy; 63:894–909, 2006. sodium phosphate, and sodium 163A, 2006. 41. Just, P. M. et al., ‘‘Reimbursement phosphates (dibasic sodium phosphate 31. Markowitz, G. S. et al., ‘‘Acute and Economic Factors Influencing monobasic sodium phosphates in a Phosphate Nephropathy Following Oral Dialysis Modality Choice around the solution dosage form administered as Sodium Phosphate Bowel Purgative: An World,’’ Nephrology Dialysis 59.4 grams (g) of sodium phosphates Unrecognized Cause of Chronic Renal Transplantation, 23(7):2365–2373, taken in two 45-milliter (mL) doses 12 Failure,’’ Journal of the American 2008. hours apart or 49.5 g of sodium Society of Nephrology, 16:3389–3396, 42. St. Peter, W., ‘‘Introduction: phosphates taken as a 45-mL dose 2005. Chronic Kidney Disease: A Burgeoning followed by a 30-mL dose 12 hours 32. Ma, R. C. et al., ‘‘Acute Renal Health Epidemic,’’ Journal of Managed later) for use as part of a bowel Failure Following Oral Sodium Care Pharmacy, 13(9):S2–S5, 2007. cleansing regimen in preparing the Phosphate Bowel Preparation in 43. Agency for Healthcare Research patient for surgery or for preparing the Diabetes,’’ Diabetes Care, January: and Quality, HCUPnet National and colon for x-ray endoscopic examination. 30(1):182–3. 2007. regional estimates on hospital use for all patients from the HCUP Nationwide * * * * * 33. Gonlusen, G. et al., ‘‘Renal Failure (d) Any OTC drug product that is not Inpatient Sample (NIS) (2006), data and Nephrocalcinosis Associated with in compliance with this section is accessed March 11, 2009. Oral Sodium Phosphate Bowel subject to regulatory action if initially Cleansing: Clinical Patterns and Renal List of Subjects introduced or initially delivered for Biopsy Findings,’’ Archives of Pathology introduction into interstate commerce 21 CFR Part 310 and Laboratory Medicine, January: after the dates specified in paragraphs 130(1):101–6, 2006. Administrative practice and (d)(1) through (d)(53) of this section. 34. Hurst, F. P. et al., ‘‘Association of procedure, Drugs, Labeling, Medical (1) May 7, 1991, for products subject Oral Sodium Phosphate Purgative Use devices, Reporting and recordkeeping to paragraphs (a)(1) through (a)(2)(i), with Acute Kidney Injury,’’ Journal of requirements. (a)(3)(i), (a)(4)(i), (a)(6)(i)(A), the American Society of Nephrology, 21 CFR Part 334 (a)(6)(ii)(A), (a)(7) (except as covered by 18:1–6, 2007. paragraph (d)(3) of this section), (a)(8)(i), 35. Brunelli, S. M. et al., ‘‘Risk of Labeling, Over-the-counter drugs. (a)(10)(i) through (a)(10)(iii), Kidney Injury Following Oral Therefore, under the Federal Food, (a)(12)(i)(A), (a)(12)(ii)(A), (a)(12)(iii), Phoshphasoda Bowel Preparations,’’ Drug, and Cosmetic Act and under (a)(12)(iv)(A), (a)(14) through (a)(15)(i),

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(a)(16) through (a)(18)(i)(A), (a)(18)(ii) FOR FURTHER INFORMATION CONTACT: Guard’s decision-making process (except as covered by paragraph (d)(22) Kathryn Holman at (202) 622–3840 (not included consideration of comments of this section), (a)(18)(iii), (a)(18)(iv), a toll-free number). submitted in response to its request for (a)(18)(v)(A), and (a)(18)(vi)(A) of this SUPPLEMENTARY INFORMATION: comments on the costs and benefits of section. expanding the existing 12-character HIN Background * * * * * in order to provide additional (53) [INSERT DATE 30 DAYS AFTER The notice of proposed rulemaking; information identifying vessels. DATE OF PUBLICATION OF THE notice of a public hearing; and ADDRESSES: The docket for this action is FINAL RULE IN THE FEDERAL withdrawal of previously proposed available for inspection or copying at REGISTER], for products subject to rulemaking that is the subject of this the Docket Management Facility (M–30), paragraph (a)(12)(ii)(B) of this section. document is under section 6049 of the U.S. Department of Transportation, Internal Revenue Code. West Building Ground Floor, Room PART 334—LAXATIVE DRUG W12–140, 1200 New Jersey Avenue, SE., Need for Correction PRODUCTS FOR OVER-THE- Washington, DC 20590, between 9 a.m. COUNTER HUMAN USE As published, the notice of proposed and 5 p.m., Monday through Friday, rulemaking; notice of a public hearing; 3. The authority citation for 21 CFR except Federal holidays. You may also and withdrawal of previously proposed part 334 continues to read as follows: find this docket on the Internet by going rulemaking (REG–146097–09) contains to http://www.regulations.gov, inserting Authority: 21 U.S.C. 321, 351, 352, 353, errors that are misleading and are in ‘‘USCG–2007–29236’’ in the ‘‘Keyword’’ 355, 360, 371. need of clarification. box, and then clicking ‘‘Search.’’ § 334.80 [Amended] Correction to Publication FOR FURTHER INFORMATION CONTACT: If 4. Section 334.80 as proposed on you have questions about this notice, Accordingly, the notice of proposed call or e-mail Mr. Jeffrey Ludwig, Coast January 15, 1985 (50 FR 2124), is rulemaking; notice of a public hearing; amended by removing ‘‘sodium Guard; telephone 202–372–1061, e-mail and withdrawal of previously proposed [email protected]. If you have phosphate/sodium biphosphate rulemaking which is the subject of FR identified in § 334.16(d)’’ from questions on viewing material in the Doc. 2011–82 is corrected as follows: docket, call Ms. Renee V. Wright, paragraph (a)(2), and by removing On page 1105, in the preamble, paragraph (b)(2) and redesignating Program Manager, Docket Operations, column 3, under the caption DATES, line telephone 202–366–9826. paragraph (b)(3) as paragraph (b)(2). 4, the language ‘‘public hearing SUPPLEMENTARY INFORMATION: On March Dated: February 3, 2011. scheduled for April 28,’’ is corrected to 17, 2008, we published a request for Leslie Kux, read ‘‘public hearing scheduled for April public comments on the costs and 27,’’. Acting Assistant Commissioner for Policy. benefits of expanding the existing On page 1107, in the preamble, [FR Doc. 2011–3091 Filed 2–10–11; 8:45 am] 12-character HIN in order to provide column 2, under the paragraph heading BILLING CODE 4160–01–P additional information identifying ‘‘Comments and Public Hearing’’, line vessels (73 FR 14193). The notice 14, the language ‘‘for April 28, 2011, specifically requested comments on: beginning at 10 a.m.’’ is corrected to DEPARTMENT OF THE TREASURY (1) The expected benefits and costs of an read ‘‘for April 27, 2011, beginning at 10 expanded HIN; (2) the manner in which a.m.’’ Internal Revenue Service the Coast Guard should exempt small LaNita VanDyke, entities and builders of high-volume, 26 CFR Parts 1 and 31 Branch Chief, Publications and Regulations low-cost vessels; (3) the estimated [REG–146097–09] Branch, Legal Processing Division, Associate collection of information burdens to Chief Counsel, (Procedure and vessel manufacturers if the current 12- RIN 1545–BJ01 Administration). character HIN regulations were revised Guidance on Reporting Interest Paid to [FR Doc. 2011–2922 Filed 2–10–11; 8:45 am] to require additional characters; and (4) Nonresident Aliens; Correction BILLING CODE 4830–01–P possible alternatives to an expanded HIN. The Coast Guard also sought AGENCY: Internal Revenue Service (IRS), specific data to support its decision- Treasury. DEPARTMENT OF HOMELAND making process about whether to ACTION: Correction to notice of proposed SECURITY initiate a rulemaking addressing an rulemaking; notice of a public hearing; expanded HIN. and withdrawal of previously proposed Coast Guard In response to the request for rulemaking. comments, we received 29 comments. 33 CFR Part 181 The Coast Guard has decided not to SUMMARY: This document contains initiate a rulemaking addressing an [Docket No. USCG–2007–29236] corrections to notice of proposed expanded HIN based on consideration rulemaking; notice of a public hearing; Hull Identification Numbers for of the comments received as well as the and withdrawal of previously proposed Recreational Vessels challenges from data uncertainty in rulemaking (REG–146097–09) that was describing, estimating, and quantifying published in the Federal Register on AGENCY: Coast Guard, DHS. potential costs and benefits of such a Friday, January 7, 2011 (76 FR 1105). ACTION: Follow-up to request for rulemaking. The proposed regulations provide comments. guidance on the reporting requirements Background for interest on deposits maintained at SUMMARY: The Coast Guard announces The Coast Guard has been looking U.S. offices of certain financial its decision to not initiate a rulemaking into the possibility of an expanded HIN institutions and paid to nonresident addressing an expanded hull for several years. In 1994, the Coast alien individuals. identification number (HIN). The Coast Guard initiated a rulemaking to create

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