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Sodium Phosphate Tablets and Acute Phosphate Nephropathy

Ann Corken Mackey, RPh, MPH1, Lanh Green, PharmD, MPH1, Keith St Amand, MD1 and Mark Avigan, MD, CM1

Am J Gastroenterol 2009;104:1903–1906; doi:10.1038/ajg.2009.342

We report 10 cases of acute phosphate From July 2006 to September 2008, It has been documented in the litera- nephropathy (APN), associated with 10 cases of APN associated with SPT ture that maintaining adequate hydra- acute renal failure (ARF), following use for bowel cleansing were reported tion and dividing the two SP doses administration of sodium phosphate to the FDA’s Adverse Event Report- by 12 hours are important to prevent tablets (SPTs) that were used as a bowel ing System (AERS) database (Table 1; intravascular volume depletion and preparation before . SPTs patients 1–7 took Visicol and patients thereby minimize the risk of APN and were first approved by the US Food and 8–10 took OsmoPrep). Note that two ARF (9–11). The product labels for Drug Administration (FDA) in Septem- cases (patients 5 and 6 in Table 1) also Visicol and OsmoPrep recommend ber 2000 for bowel cleansing at a dose of have been reported in the literature; that patients take a total of at least 112 60 g (40 tablets) in two divided doses with no additional cases have been pub- ounces and 64 ounces of liquid, respec- adequate hydration (trade name Visi- lished (2,4). Renal in these 10 tively, and that divided doses be taken col). The proposed mechanism of action patients revealed (cal- in the evening and morning before of SPTs is an osmotic effect. The Visicol cium phosphate crystal deposition in colonoscopy (7,12). In this case series, product was subsequently reformulated, the distal tubules and collecting ducts). there is little reported information on because it was found that one of the Decreased intravascular volume caused whether patients took SPTs correctly or excipients, microcrystalline cellulose, was by bowel cleansing may also contribute incorrectly (information of this type is leaving a residue in the colons of some to an increase in the phosphate concen- typically not provided in adverse-event patients that impaired visibility during tration in renal tubular fluid. reports and is difficult to obtain on fol- their colonoscopy (1). In addition, the The patients in this case series all had low-up inquiry); patient 9 separated the manufacturer of this product provided at least one underlying risk factor for two SP doses by 3 hours only. data demonstrating that patients’ bowels ARF, and most had more than one (Table Four patients in this case series were effectively cleansed with the use of 1). In addition to decreased intravascu- required dialysis. To date, there have 48 g (32 tablets) of sodium phosphate (SP) lar volume as described above, other been no reported deaths or kidney trans- in divided doses with adequate hydration. risk factors for ARF include preexisting plantations associated with SPT use. With these doses, a new product (trade renal insufficiency, , diabe- From 1 January 2001 through 30 Sep- name OsmoPrep) was approved by the tes mellitus, advanced age, underlying tember 2008, 2,297,958 and 1,329,497 FDA in March 2006. Both products are , and concomitant prescriptions were dispensed for Visi- marketed by Salix Pharmaceuticals at a medications that affect renal perfusion col and for OsmoPrep, respectively dose of 1.5 g SP per tablet. Note that APN or function (e.g., angiotensin-converting (Figure 1).​ These data were obtained from also has been associated with the use of enzyme inhibitors (ACEIs), angiotensin the SDI Vector One database, which mea- SP oral solution for bowel cleansing (2). receptor blocker (ARB) drugs, nonsteroi- sures retail dispensing of prescriptions. This article addresses the SPT dosage dal anti-inflammatory drugs (NSAIDs), In addition to the 10 cases of APN, form only. (SP oral solution is no longer or ) (5,6). Patients with chronic the AERS has received 31 cases reported available over the counter for the indica- inflammatory bowel disease may have as ARF associated with SPT use. These tion of bowel cleansing. CB Fleet is apply- enhanced absorption of SP (7). One ret- patients did not have a to ing for prescription status (3).) rospective case-controlled study using document nephrocalcinosis; therefore, records from the University of Pennsyl- the mechanism of renal failure with 1 Office of Surveillance and Epidemiology, Food vania health-care system found a signifi- SPT exposure could not be verified. Of and Drug Administration, Silver Spring, Maryland, USA. Correspondence: Ann Corken Mackey, RPh, cant association between ACEI/ARB use these 31 cases, 12 patients used Visicol, MPH, Office of Surveillance and Epidemiology, and in patients with 4 patients used a foreign SP product Food and Drug Administration, Building 22, baseline serum creatinines of ≤1.5 mg/ (1 g per tablet, total dose of 50 g in Room 3472, 10903 New Hampshire Avenue, Silver Spring, Maryland 20993, USA. dl who received SP for bowel cleansing divided doses with adequate hydration), E-mail: [email protected] before colonoscopy (8). and 15 patients used OsmoPrep. A total

© 2009 by the American College of The American Journal of Gastroenterology 1904 the red section 10 , male; 63/F 10.6 ime to NSAID T M 14 Days b Screening Jan. 2008 Not stated Not stated HO, dialysis

2 9 HO 0.5 N, hypertension; 58/F T 21 Days doses of 3 hours) Where reported, baseline creati - CD, ACEI, Apr. 2007 Apr. Abd. pain, 30 and 18 d 48 (Divided possible CD separated by NSAID (p.r.n.) HTN, possible a 8 3.1 1.1 58/F , hospitalization; H O 15 Days Oct. 2007 Not stated Not stated HO, dialysis HTN, NSAID, a 7 7.3 1.2 65/M <12 Days Not stated HTN, DM, 48 (Over a Dec. 2005 HO, dialysis gastrectomy, gastrectomy, 2-day period) ACEI, diuretic ynne Yao for her expertise in the review of these cases.) ynne Yao

Normal serum value = 0.5–1.5 mg/dl. , mellitus; F, female;, diabetes H mellitus; F, c M 6 2.3 1.7 44/M NSAID RI, HTN, 2 Months Not stated Feb. 2003 and 18 the 48 (Divided the evening colitis, ACEI (high dose), Bloody stool next morning) doses of 30 in 5 1.8 0.9 60/F dose) 4 Months Apr. 2005 Apr. Screening Not stated 42 (As one HTN, ACEI ne case reported as moderate and extensive luminal in a 53-year-old woman who took 4 O 55/F WNL NSAID 4 Range Abd. pain Oct. 2007 Not stated Not stated HTN, ARB, HO, dialysis , sodium phosphate tablet; WN L within normal limits. 3 HO 4.5 66/F 1 Day Screening Not stated Not stated Mar. 2006 Mar. HTN, ACEI 1 2 70/F dose) 11 Days 2.6 – 2.8 Apr. 2006 Apr. Not stated Not stated 30 (As one HTN, ACEI c 1 HO 1.2 2.8 67/F diuretic HTN, DM I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CD, disease; Crohn’s D Not stated Not stated Not stated Feb. 2006 E type 2, ACEI, Summary of case reports acute phosphate nephropathy associated with use sodium tablets for bowel cleansing as r eported to d (after use b In addition to nephrocalcinosis, the biopsy for patient 7 showed intermediate stages of diabetic , and the biopsy for patient 8 showed moderate chronic tubulointerstitial . In addition to nephrocalcinosis, the biopsy for patient 7 showed intermediate stages of diabetic glomerulopathy, N S AID, nonsteroidal anti-inflammatory drug; RI, renal insufficiency; P T Abd, abdominal; AC Attempts were made to contact reporters for follow-up information on these cases. a pathy in a 69-year-old woman have been excluded because nephrocalcinosis woman have been excluded because nephrocalcinosis O smoPrep, and one case reported as acute tubular necrosis with intratubular consistent phosphate nephro pathy in a 69-year-old was not reported (these cases are included in our discussion of patients who developed acute renal failure). ( S pecial thanks to L detection is reported based on when the patient had symptoms of renal impairment, sought medical advice, and was tested. administration with the following exceptions: time frame not specified for patient 1, and baseline for patient 4 was taken nine laboratory values were measured in samples obtained up to 3 months before S P T administration with the following exceptions: time frame not specified for patient 1, and baseline 4 was taken 4–5 months before S P T administration. Outcome Serum creatinine values (mg/dl) SPTs (grams) SPTs to detec - Time tion Reason for colonoscopy Date of colonoscopy Age/sex of preparation) Risk factors for renal dysfunction the Food and Drug Administration’s Adverse Event Reporting System from July 2006 to September 2008 the Food and Drug Administration’s Table 1. Table Patient no. Baseline Value mea - Value sured after procedure

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association of APN and SP product use for bowel cleansing on its Web site (14). OsmoPrep Since May 2006, the FDA has received Visicol additional cases of APN and ARF associ- ated with SPT use. As a result of this new iptions safety information, the FDA has required the manufacturer of prescription SPT products (Visicol and OsmoPrep) to

otal prescr strengthen product labeling to include T a boxed warning, provide a medication guide for patients, and implement a risk evaluation and mitigation strategy to ensure that the benefits of SP prod- ucts outweigh the risks. The FDA is also Quarter year requiring that a postmarketing clinical trial be conducted to further assess the risk of acute kidney injury with use of Figure 1. Drug-use data: total number of dispensed prescriptions for sodium phosphate tablets (i.e., Visicol, OsmoPrep) in outpatient retail pharmacies, 1 January 2001 through 30 September these products. For additional informa- 2008. (From SDI Vector One: National; data extracted January 2009 by Patty Greene, Drug Utilization tion, see the December 2008 FDA Alert Data Analysis, Division of Epidemiology, Office of Surveillance and Epidemiology, US Food and Drug at the FDA’s website (15). Administration.) The patients in this case series had potentially confounding medical condi- of 27 cases were reported from domestic reported for 6 patients). Baseline creati- tions or were taking concomitant medi- sources, and 4 cases were reported from nine values were reported for 13 patients cations that put them at increased risk foreign sources. The patients ranged (these were within normal limits except for ; however, a causal or in age from 45 to 77 years (mean 65 for one patient with preexisting renal contributory role of SPTs cannot be ruled years; age not reported for 1 patient); 22 insufficiency); postprocedure creatinine out. It appears that some patients, espe- patients were female, and 9 patients were values were reported for 20 patients and cially those with risk factors, developed male. The doses used ranged from 30 to ranged from 1.2 to 10 mg/dl (mean 5.7 APN with doses as small as 30 g of SP. 60 g (mean 49 g; n=23; dose was not mg/dl). Two patients’ creatinine values Clinicians should be aware when pre- reported for 8 patients). It was reported were reported as “elevated”; postproce- scribing SPTs that some patients who that 21 patients used a split-dose regi- dure creatinine values were not included developed renal injury did not present men (3 of the 21 patients split their dose in reports for 9 patients. with symptoms of APN for up to several with an interval of only 3–4 hours); 12 The AERS is a spontaneous, volun- months after using SPTs. Until further patients were reported to have followed tary surveillance system that collects information is available (e.g., a recently hydration directions (information on reports of adverse events for US mar- proposed clinical trial by the FDA (15)), dose and hydration was not reported keted medicinal products. Manufactur- there is insufficient information to make for the remaining patients). Of the 31 ers holding New Drug Applications or global recommendations regarding patients, 4 patients used additional laxa- Biologic Licensing Applications must standard pre- and postprocedure renal- tives with SPTs (i.e., bisacodyl, magne- submit adverse-event reports to the function testing for patients who may sium citrate). The time to ARF detection AERS according to the Code of Federal be at risk. In addition, the importance of after SPT use ranged from 0.5 to 60 days Regulations. Data from the AERS can- taking SPTs correctly (i.e., with adequate (mean 6.3 days; n=25; information was not be used to estimate true incidence hydration and splitting the two SP doses not provided for 6 patients). The follow- rates of events, because the numerator by 12 hours) should be stressed in order ing risk factors for renal dysfunction is underestimated and the denominator to reduce the risk of developing APN were reported (not mutually exclusive): can only be estimated. The AERS is sub- and ARF. hypertension (22 patients), diabetes ject to underreporting; fewer than 10% mellitus (9 patients), preexisting renal of adverse events are reported to the CONFLICT OF INTEREST insufficiency (2 patients), inflammatory FDA, so there may be additional cases of Guarantor of the article: Ann Corken bowel disease (2 patients), ACEI/ARB APN associated with SPT use for bowel Mackey, RPh, MPH. use (20 patients), diuretic use (8 patients), cleansing (13). Specific author contributions: Each NSAID use (7 patients), and contrast dye The manufacturer of SPTs added APN author contributed to the draft and use (2 patients). At least 25 patients were to the warnings section of the labels for review of this article. hospitalized for ARF, including 4 patients its products in March 2006. At that time, Financial support: None. who required dialysis (outcome was not the FDA posted information about the Potential competing interests: None.

© 2009 by the American College of Gastroenterology The American Journal of Gastroenterology 1906 the red section

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