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Fleet’s Expert Witness Discusses The Association Of Acute Phosphate Nephropathy With Fleet’s Phospho-Soda Product

Posted in Misc. Drugs

Fleet’s expert provides some good background information regarding Phospho-Soda and Phosphate Nephropathy, as well as other kidney troubles:

In March 2003, Dr, Glen Markowitz, a nephropathologist at Columbia University, reported to C.B. Fleet several cases of nephrocalcinosis that he thought might be associated with sodium phosphate use. I was invited by Sherrie Scott, RN to attend a meeting with Dr. Markowitz at Columbia University Hospital in New York City on April 11, 2003. In attendance were Ms. Scott and Joseph Kanapka, PhD from Fleet and Dr.'s Markowitz, Radhakrishnan and D'Agati from Columbia. We reviewed the clinical histories of the five cases of “acute nephrocalcinosis” that Dr. Markowitz had identified, including the dosing of sodium phosphate, hydration, concomitant medications, and selected histopathology. We were informed that all of the patients had been diagnosed after February 1, 2003. At the time of our meeting, the dosing intervals of sodium phosphate and hydration received during bowel preparation were unknown In four of the five patients who received their preparation at home. A main focus of Dr. Markowitz and his colleagues was whether there was an interaction between sodium phosphate and medications that can affect renal perfusion, including angiotensin converting enzyme inhibitors (ACE-I), angiotensin receptor blockers (ARB), and diuretics.

To date, a total of 27 cases have been reported in full manuscript form in the scientific literature, 25 of which were associated with oral sodium phosphate solution and two with sodium phosphate tablets. In addition, I am aware of additional cases reported in abstract form or reported directly to the pharmaceutical manufacturers or the FDA. Most of the subjects reported in the literature had normal renal function prior to ingestion of sodium phosphate. In the largest case series published, renal failure occurred between 1 day and 5 months after colonoscopy, with a median presentation 1 month following the bowel preparation.[FN45] In 23 cases associated with sodium phosphate solution and reported in detail[FN43],[FN45],[FN46],[FN50], it is reported that one subject received an overdose of sodium phosphate while the other subjects took a split-dose regimen of 90-mL.

Ellen Kittredge Scott, Esq.

Pepper Hamilton LLP

3000 Two Logan Square

18th and Arch Streets

Philadelphia, PA 19103-2799

Purpose

The following is a review of the subjects on which I may testify on behalf of C.B. Fleet Company, Inc. in litigation pertaining to Fleet Phospho-soda(R), including general medical principles related to gastroenterology and colonoscopy. The information and opinions presented are based on a review of pertinent scientific literature; pharmaceutical resources; publicly available documents distributed by the Food and Drug Administration and the National Cancer Institute; certain expert reports, complaints, and interrogatories; and my experience and training as a gastroenterologist and medical consultant to C.B. Fleet.

The Role of Colonoscopy

Colorectal cancer is the second leading cause of cancer-related mortality in the United States.[FN1] Approximately 6% of Americans will develop colorectal cancer in their lifetimes.[FN2] In 2007, an estimated 153,760 new cases of colorectal cancer were diagnosed in the United States and 52,180 died of this disease.[FN3] Regrettably, the majority of these cases are preventable with proper screening.

FN1. Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, Feuer EJ. Thun MJ. Cancer statistics, 2005. CA Cancer J Clin 2005:55:10-30

FN2. Ries LAG, Eisner MP, Kosary CL, et al., eds.: SEER Cancer Statistics Review, 1975-2002. Bethesda, MD: National Cancer Institute, 2005

FN3. National Cancer Institute: Colon and Rectal Cancer. Washington, D.C., 2007. http://www.cancer.gov/cancertopics/types/colon-and-rectal. Last accessed January 9, 2008

Colonoscopy is widely recognized as the most effective method of screening for colorectal cancer in average-risk individuals age 50 and above and in higher risk patients, such as those with a family history of colorectal neoplasia.[FN4] Most colorectal cancers are thought to arise from polyps that can be detected and removed before they become malignant.[FN5],[FN6] Results from the National Polyp Study demonstrate that removal of polyps by colonoscopy decreases the expected incidence of colorectal cancer by up to 90%.[FN7]

FN4. Rex DK, Johnson DA, Lieberman DA, et al. Colorectal cancer prevention 2000: screening recommendations of the American College of Gastroenterology. Am J Gastroenterol 2000;95:868-77

FN5. Hill MJ, Morson BC, Bussey HJ: Aetiology of adenoma-carcinoma sequence in large bowel. Lancet 1978;1(8058): 245-7

FN6. Voge??stein B, Fearon ER, Hamilton SR, et al. Genetic alterations during colorectal-tumor development. N Engl J Med. 1988:319:525-32

FN7. Winawer SJ, Zauber AG, Ho MN, et a. Prevention of colorectal cancer by colonoscopic polypectomy. The National Polyp Study Workgroup. N Engl J Med 1993;329:1977-81

The sensitivity of colonoscopy as a screening method for polyps is directly related to the adequacy of bowel preparation.[FN8],[FN9] Patients with poor bowel preparation for colonoscopy have a lower rate of detection of both small[FN8] ,[FN9] and large[FN9] precancerous polyps. These missed polyps could develop into colon cancer if not removed during the screening colonoscopy. In addition, colonoscopy exams performed in patients with suboptimal bowel preparation take longer to perform and are more likely to be incomplete than exams in patients with adequate preparation.[FN9] Economic analyses at a community hospital and a university hospital in Indiana have shown that poor colon cleansing prior to colonoscopy increases the cost of colorectal cancer screening by 10.7% to 21.8%, depending on the incidence of poor preparation.[FN10] Therefore, proper bowel cleansing is critical to the sensitivity and economic feasibility of colonoscopy as a screening method. In addition, it has been shown that the bowel preparation is the single greatest deterrent to undergoing a screening colonoscopy[FN11]; therefore, efforts to improve the tolerability of the bowel cleansing process might increase colonoscopy utilization rates.

FN8. Harewood GC, Shar??a VK, de Garmo P. Impact of colonoscopy preparation quality on detection of suspected colonic neoplasia. Gastrointest Endoso 2003:58:76-9

FN9. Froehlich F, Wiet??sbach V, Gonvers JJ, Burnand B, Vader JP. Impact of colonic cleansing on quality and diagnostic yield of colonoscopy: the European Panel of Appropriateness of Gastrointestinal Endoscopy European multicenter study. Gastrointest Endosc 2005:61:378-84

FN10. Rex DK, Imperiale TF, Latinovich DR, et al. Impact of bowel preparation on efficiency and costs of colonoscopy. Am J Gastroenterol 2002; 97:1587-90

FN11. Harewood GC, Wiersema MJ, Melton LJ 3rd. A prospective, controlled assessment of factors Influencing acceptance of screening colonoscopy. Am J Gastroenterol 2002;97;3186-94

Methods of Bowel Preparation

Over the last 30 years, major advances in the science of bowel preparation have been achieved. Early methods of colon cleansing for colonoscopy evolved from preparations used for surgery and radiology procedures, including prolonged fasting, large-volume gut lavage with concentrated salt solutions, and enemas.[FN12] In general, patients tolerated these regimens poorly, and clinically significant electrolyte and intravascular fluid shifts often limited their use.[FN12] Currently, the two most widely used methods of bowel preparation are polyethylene glycol with electrolyte solution (PEG-ELS) and sodium phosphate, which are the focus of this review.

FN12. Wexner SD, Beck DE, Baron TH, et al. A consensus document on bowel preparation before colonoscopy: Prepared by a Task Force from The American Society of Colon and Rectal Surgeons (ASCRS), the American Society for Gastrointestinal Endoscopy (ASGE), and the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES). Gastrointest Endosc 2006:63:894-909

In 1980, Fordtran and colleagues reported the development of a 4-liter gut lavage solution containing polyethylene glycol and electrolytes for use prior to diagnostic studies that resulted in minimal electrolyte and fluid absorption or secretion.[FN13] PEG-ELS is an Isotonic bowel cleansing preparation that is poorly absorbed; it exerts a laxative effect by sequestering water within its molecular structure.[FN13],[FN14] The addition of electrolytes balanced to equal concentrations in serum results in minimal metabolic and intravascular volume effects. This preparation quickly became accepted as the standard for bowel cleansing prior to colonoscopy. However, between 19% and 63% of subjects are unable to complete this preparation due to the taste of the solution and the large volume of fluid that must be ingested.[FN15],[FN16],[FN17] A reduced volume (2L) PEG-ELS regimen combined with bisacodyl tablets (HalfLytely(R)) has been shown to produce equivalent bowel cleansing and superior efficacy compared to standard 4L PEG-ELS.[FN18] However, this study also showed that 6.5% of subjects in the HalfLytely group demonstrated inadequate preparation for exam, an unacceptably high percentage. A newer low-dose PEG-ELS bowel prep using ascorbic acid as an adjuvant (MoviPrep) has received FDA approval. This 2-liter preparation is provided either the evening before the colonoscopy or as a split-dose the evening prior and morning of the procedure. A randomized controlled trial of MoviPrep vs. oral sodium phosphate solution found that the two preparations offer comparable efficacy.[FN19] However, in this study the sodium phosphate was administered entirely the day before the procedure, potentially limiting its effectiveness. A bowel preparation consisting of polyethylene glycol 3350 without electrolytes (Miralax(R)) mixed in a beverage of choice (e.g. 32 to 64 ounces of Gatorade(R)) has been recommended as a better-tasting alternative to PEG-ELS, particularly in children[FN20]; however, there are no published, randomized trials in adults evaluating this preparation.

FN13. Davis GR, Santa Ana CA, Morawski SG, et al. Development of a lavage solution with minimal water and electrolyte absorption or secretion. Gastroenterology 1980:78:991-5

FN14. Schiller LR. Clinical pharmacology and use of laxatives and lavage solutions. J Clin Gastroenterol 1999;28:11-8

FN15. Cohen SM, Wexner SD, Binderow SR, Nogueras JJ, Daniel N, Ehrenpreis ED, Jensen J, Bonner GF, Ruderman WB. Prospective, randomized, endoscopic-blinded trial comparing precolonoscopy bowel cleansing methods, Diseases of the Colon & Rectum 1994;37:689-96

FN16. Golub RW, Kerner BA, Wise WE Jr., at al. Colonoscopic preparations – which one? A blinded. prospective, randomized trial. Dis Colon Rectum 1995; 58:594-7

FN17. Oliveira L, Wexner SD, Daniel N, et al. Mechanical bowel preparation for elective colorectal sugery. A prospective, randomized, surgeon-blinded trial comparing sodium phosphate and PEG-based oral lavage solutions. Dis Colon Rectum 1997;40:585-91

FN18. DiPalma JA, Wolff BG, Meagher A, et al. Comparison of reduced volume versus four liters sulfate-free electrolyte lavage solutions for colonoscopy colon cleansing. Am J Gastroenterol. 2003;98:2187-91

FN19. Bitoun A, Ponchon T, Barthet M, Coffin B, Dugue C, Halphen M on behalf of the Norcot Group. Results of a prospective randomised multicentre controlled trial comparing a new 2-L ascorbic acid plus polyethylene glycol and electrolyte solution vs. sodium phosphate solution in patients undergoing elective colonoscopy. Ailment Pharmacol Ther 2008;24:1631-42

FN20. Pashankar DS, Uc A, Bishop WP. Polyethylene glycol 3350 without electrolytes: a new safe, effective, and palatable bowel preparation for colonoscopy in children. J Pediatr 2004;144:358-62

The safety and efficacy of sodium phosphate as a pre-colonoscopic bowel preparation was demonstrated by the 1990 study from Vanner and colleagues.[FN21] Compared to PEG-ELS, oral sodium phosphate solution was superior in bowel cleansing effectiveness and tolerability. The principle advantage of sodium phosphate is the smaller volume of medication required – 90 mL in divided doses versus 4 liters for PEG-ELS. Sodium phosphate is an osmotic laxative that is hypertonic relative to serum. It acts by drawing water into the lumen of the gut, following an osmotic gradient. Each 45-mL dose of sodium phosphate has been estimated to induce entry of up to 1.8L of fluid into the gut lumen.[FN22] Therefore, adequate hydration is important to attenuate the fluid loss that can occur with any osmotic laxative.[FN12],[FN35] The additional hydration recommended with a sodium phosphate preparation includes clear liquids of the patient's own choosing rather than a large volume of medication; in general, this is more acceptable to patients than consuming a large volume gut lavage.

FN21. vanner SJ, MacDonald PH, Paterson WG, Prentice RS, Da Costa LR. Beck IT. A randomized prospective trial comparing oral sodium phosphate with standard polyethylene glycol-based lavage solution (Golytely) in the preparation of patients for colonoscopy. Am J Gastroenterol 1990:85:422-7

FN22. Schiller L. Clinical pharmacology and use of laxatives and lavage solutions. J Clin Gastroenterol 1999:28:11-18

FN35. Hookey LC, Depew WT, Vanner S. The safety profile of oral sodium phosphate for colonic cleansing before colonoscopy in adults, Gastrointest Endosc 2002:56:895-902

In meta-analyses of published, randomized controlled trials, sodium phosphate solution demonstrates superior tolerability and equivalent or better bowel cleansing effectiveness when compared to PEG-ELS.[FN23],[FN24] These analyses show that there have been no published, randomized controlled trials demonstrating that a standard 4-liter PEG-ELS preparation is superior to a divided dose of sodium phosphate when the second dose of sodium phosphate is given on the morning of colonoscopy.[FN24] Split-dosing of sodium phosphate is critical to achieve proper cleansing of the ascending colon since bile and small intestinal secretions accumulate overnight and might obscure the colonic mucosa if the second dose of medication is not administered the morning of the procedure. Split-dosing of PEG-ELS Is now generally accepted as superior to single-dose preparation as well.[FN25]

FN23. Hsu CW, Imperiale TF. Meta-analysis and cost comparison of polyethylene glycol lavage versus sodium phosphate for colonoscopy preparation. Gastrointestinal Endoscopy 1998:48:276-82

FN24. Tan JJY, Tjandra JT. Which Is the optimal bowel preparation for colonoscopy – a meta-analysis. Colorectal Dis. 2006;8:247-58

FN25. Aoun E, Abdul-Baki H, Azar C, Mourad F, Barada K, Berro Z, Tarchichi M, Sharara Al. A randomized single-blind trial of split-dose PEG-electrolyte solution without dietary restriction compared with whole dose PEG-electrolyte solution with dietary restriction for colonoscopy preparation. Gastrointest Endosc. 2005 Aug:62(2):213-8

Sodium phosphate is currently available in both liquid (Phospho-soda(R)) and tablet (OsmoPrepTM) forms. The current recommended dosing regimens for sodium phosphate bowel preparation include 60- to 90-mL of oral sodium phosphate solution or 32 tablets of OsmoPrep In divided doses. Each 45-mL dose of liquid Phospho-soda contains 21.6g monobasic sodium phosphate monohydrate and 8.1g dibasic sodium phosphate in a stable, buffered aqueous solution.[FN26],[FN27] A 45-mL dose of Phospho-soda is approximately equivalent in sodium phosphates content to 20 tablets of OsmoPrep. Sodium phosphate tablets have been shown to be better tolerated than PEG-ELS and equally efficacious for bowel cleansing prior to colonoscopy.[FN28]

FN26. Physician's Desk Reference, 52nd ed. Montvale, NJ: Medical Economics Data; 1998:996

FN27. Physician's Desk Reference, 60th ed. Montvale, NJ: Medical Economics Data:2006:1170-2

FN28. Kastenberg D, Chasen R, Choudhary C, et al. Efficacy and safety of sodium phosphate tablets compared with PEG solution in colon cleansing: Two identically designed, randomized, controlled, parallel group, multicenter phase III trials. Gastrointest Endosc 2001:54:705-13

Safety of Bowel Preparation

All bowel preparation agents have been associated with adverse events. Barriers to safe colon preparation include improper dosing, incomplete patient instructions, inadequate hydration, lack of awareness of medical contraindications to certain products, and patient noncompliance.

PEG-ELS is a large-volume cleansing agent (2 – 4L); as such, its side effects may be related to distension of the gut that occurs as a consequence of the volume of fluid ingested for bowel cleansing. Abdominal pain and fullness are more frequent with PEG-ELS than with sodium phosphate.[FN24] As with any bowel preparation agent, PEG-ELS Is contraindicated in known or suspected bowel obstruction; additional contraindications include ileus, gastric retention, bowel perforation, toxic colitis, and toxic megacolon.[FN29] Bowel perforation has occurred in a patient with non-obstructive diverticulosis[FN30], and fatal pulmonary edema has been described when the product is aspirated (often in the setting of nasogastric administration).[FN31],[FN32] Although PEG-ELS is thought to be safe in patients with impaired renal function, rare fatal effects on serum sodium have been described in two patients with end-stage renal disease who received a standard dose of PEG-ELS[FN33]; it has been hypothesized that a syndrome of inappropriate antidiuretic hormone secretion developed in these patients due to profound nausea and vomiting. Altered serum sodium and seizure have been described recently in a patient with no preexisting renal disease who took a PEG-3350 preparation mixed with Gatorade.[FN34]

FN24. Tan JJY, Tjandra JT. Which Is the optimal bowel preparation for colonoscopy – a meta-analysis. Colorectal Dis. 2006;8:247-58

FN29. GoLYTELY(PEG-3350 and Electrolytes for Oral Solution) Full Prescribing Information, Braintree Pharmaceuticals. Available at http:/ www.nulytely.com/pdf/Golytely_Pres_Info.pdf. Accessed August 16, 2006

FN30. Langdon DE. Colonic perforation with volume laxatives. Am J Gastroenterol 1996:91:622-3

FN31. de Graaf P, Slagt C, de Graaf JLCA, Loffeld, RJLF. Fatal aspiration of polyethylene glycol solution. Neth J Med 2006;64:196-8

FN32. Marschall H-U, Bartels F, et al. Life-threatening complications of nasogastric administration of polyethylene glycol-electrolyte solutions (Golytely) for bowel cleansing. Gastrointest Endosc 1998:47:408-10

FN33. Ayus JC, Levine R, Arieff Al. Fatal dysnatraemia caused by elective colonoscopy. BMJ 2003:326:382-4

FN34. Nagler J, Poppers D, Turetz M. Severe hyponatremia and seizure following a polyethylene glycol-based bowel preparation for colonoscopy. J Clin Gastroenterol 2006;40:558-9

Since 1990, there have been numerous published clinical studies that address the safety of sodium phosphate.[FN35] Sodium phosphate may cause changes in intravascular volume and serum electrolytes just like other osmotic laxatives. The general practice has been to provide sodium phosphate in divided doses at least 10 hours apart to minimize the risk of electrolyte shifts; however, studies of dosing intervals as short as 5 hours have demonstrated acceptable safety.[FN35],[FN36] Hydration is emphasized during bowel preparation with sodium phosphate.[FN26],[FN27],[FN35] While orthostatic hypotension has been reported in up to 16% of study subjects receiving a standard split-dose regimen of sodium phosphate, the incidence of orthostatic changes has not been demonstrated to be significantly different in studies comparing sodium phosphate to PEG-ELS.[FN35] Serum electrolyte abnormalities associated with sodium phosphate use include hypernatremia, hypokalemia, hyperphosphatemia, and hypocalcemia.[FN35],[FN37],[FN38],[FN39] When administered properly in the correct dosage, electrolyte changes attributable to sodium phosphate are generally transient and clinically inconsequential.[FN35],[FN40]

FN26. Physician's Desk Reference, 52nd ed. Montvale, NJ: Medical Economics Data; 1998:996

FN27. Physician's Desk Reference, 60th ed. Montvale, NJ: Medical Economics Data:2006:1170-2

FN35. Hookey LC, Depew WT, Vanner S. The safety profile of oral sodium phosphate for colonic cleansing before colonoscopy in adults, Gastrointest Endosc 2002:56:895-902

FN36. Huynh T, Vanner 8, Paterson W. Safety profile of 5-h oral sodium phosphate regimen for colonoscopy cleansing: lack of clinically significant hypocalcemia or hypovolemia. Am J Gastroenterol 1995:90:104-7

FN37. U.S. Food and Drug Administration, Center for Drug Evaluation and Research. Science backgrounder: Safety of sodium phosphates oral solution. Rockville, MD: U.S. Food and Drug Administration, 2001, Available at http:/ www.fda.gov/cder/drug/safety/sodiumphospate.htm. Accessed July 26, 2006

FN38. DiPalma JA, Buckley SE, Warner BA, Culpepper RM: Biochemical Effects of Oral Sodium Phosphate. Dig Dis Sci 41:749-753,1996

FN39. Lieberman DA, Ghormley J, Flora K: Effect of Oral Sodium Phosphate Colon Preparation on Serum Electrolytes in Patients with Normal Serum Creatinine. Gastrointest Endoscopy 1996;43:467-469

FN40. Fleet Study F00.020, Data on File, C.B. Fleet Company, Inc.

Through 2002, the majority of clinically significant electrolyte disturbances and adverse events reported In the medical literature, including volume depletion, metabolic acidosis, renal failure, tetany, and death, have occurred in patients who were prescribed a dose of sodium phosphate solution exceeding 90-mL in a 24-hour period, in patients who did not receive proper hydration during bowel preparation, or in patients with a medical contraindication to the product.[FN35] Although high doses of sodium phosphate have been associated with adverse events, Barclay reported that subjects using a triple-dose (135-mL) regimen of liquid sodium phosphate suffered no adverse sequelae and had similar rates of subclinical orthostasis compared to subjects taking a standard two-dose (90-mL) regimen.[FN41]

FN41. Barclay RL, Safety, efficacy, and patient tolerance of a three-dose regimen of orally administered aqueous sodium phosphate for colonic cleansing before colonoscopy. Gastrointest Endosc. 2004:60:527-33

How Gastroenterologists Prescribe Bowel Preparation

The techniques used for bowel preparation prior to colonoscopy likely vary across the country based on local and regional preferences. Since gastroenterologists first learn about bowel preparation during their fellowship training programs, the use of one bowel cleansing regimen over another often reflects the lessons learned during training. Additional modifications to the regimens may then be made based on anecdotal experience, feedback from patients, new scientific literature, and educational symposia at local and national meetings. In my opinion, marketing materials and advertising probably play only a limited role in the education of physicians prescribing bowel cleansing agents and serve primarily as a resource for identifying new products.

The endoscopist prescribes a specific bowel cleansing regimen for a particular patent just like any prescription medication, even for over-the-counter medications, such as Phospho-soda and magnesium citrate. Most endoscopists create their own bowel preparation instruction sheets that they distribute to patients. The regimen includes the dosage of bowel cleansing agent(s), the dosage interval, hydration, and the recommended diet preceding the colonoscopy. A medical history must be obtained prior to recommending a bowel preparation product to assure the absence of any medical contraindications. Both PEG-ELS and sodium phosphate have warnings and precautions indicated in their labeling, and these should be considered when deciding which product to use. No matter which preparation is selected, volume depletion can occur with bowel cleansing and may cause deleterious effects, including alterations in electrolytes and renal injury.

Acute Phosphate Nephropathy

Recently, several case reports of acute renal failure and nephrocalcinosis associated with the use of sodium phosphate bowel preparations have been reported in the medical literature.[FN42],[FN43],[FN44],[FN45],[FN46],[FN47] ,[FN48],[FN49] This syndrome has been termed “acute nephrocalcinosis” or “acute phosphate nephropathy” to distinguish it from typical calcium phosphate deposition in the kidney, which usually occurs in chronic disease states such as hyperparathyroidism, prolonged hypercalcemia, sarcoidosis, or renal tubular acidosis.[FN43],[FN44]

FN42. Desmeules 8, Bergeron MJ, Isenring P. Acute phosphate nephropathy and renal failure. N Engl J Med 2003;349:1006-7

FN43. Markowitz GS, Nasr SH, Klein P, Anderson H, Stack JI, Alterman L, Price B, Radhakrishnan J, D'Agati VD. Renal failure due to acute nephrocalcinosis following oral sodium phosphate bowel cleansing. Hum Pathol 2004:35:675-84

FN44. Markowitz GS, Whelan J, D'Agati VD. Renal failure following bowel cleansing with a sodium phosphate purgative. Nephrol Dial Transplant 2005; 20:850-1

FN45. Markowitz GS, Stokes MB, Radhakrishnan J, D'Agati VD. Acute phosphate nephropathy following oral sodium phosphate bowel purgative: an underrecognized cause of chronic renal failure. J Am Soc Nephrol 2005;16:3389-96

FN46. Gonlusen G, Akgun H, Ertan A, Olivero J, Truong LD. Renal failure and nephrocalcinosis associated with oral sodium phosphate bowel cleansing: clinical patterns and renal biopsy findings, Arch Pathol Lab Med 2006;130:101-6

FN47. Manley P. Somerfield J, Simpson I, Barber A, Zwi J. Bilateral uraemic optic neuritis complicating acute nephrocalcinosis. Nephrol Dial Transplant. 2006;21(10):2957-8

FN48. Beyea A, Block C, Schned A. Acute phosphate nephropathy following oral sodium phosphate solution to cleanse the bowel for colonoscopy. Am J Kidney Dis 2007;50:151-4

FN49. Carl DE, Sica DA. Acute phosphate nephropathy following colonoscopy preparation. Am J Med Sci. 2007;334:151-4

In March 2003, Dr, Glen Markowitz, a nephropathologist at Columbia University, reported to C.B. Fleet several cases of nephrocalcinosis that he thought might be associated with sodium phosphate use. I was invited by Sherrie Scott, RN to attend a meeting with Dr. Markowitz at Columbia University Hospital in New York City on April 11, 2003. In attendance were Ms. Scott and Joseph Kanapka, PhD from Fleet and Dr.'s Markowitz, Radhakrishnan and D'Agati from Columbia. We reviewed the clinical histories of the five cases of “acute nephrocalcinosis” that Dr. Markowitz had identified, including the dosing of sodium phosphate, hydration, concomitant medications, and selected histopathology. We were informed that all of the patients had been diagnosed after February 1, 2003. At the time of our meeting, the dosing intervals of sodium phosphate and hydration received during bowel preparation were unknown In four of the five patients who received their preparation at home. A main focus of Dr. Markowitz and his colleagues was whether there was an interaction between sodium phosphate and medications that can affect renal perfusion, including angiotensin converting enzyme inhibitors (ACE-I), angiotensin receptor blockers (ARB), and diuretics.

To date, a total of 27 cases have been reported in full manuscript form in the scientific literature, 25 of which were associated with oral sodium phosphate solution and two with sodium phosphate tablets. In addition, I am aware of additional cases reported in abstract form or reported directly to the pharmaceutical manufacturers or the FDA. Most of the subjects reported in the literature had normal renal function prior to ingestion of sodium phosphate. In the largest case series published, renal failure occurred between 1 day and 5 months after colonoscopy, with a median presentation 1 month following the bowel preparation.[FN45] In 23 cases associated with sodium phosphate solution and reported in detail[FN43],[FN45],[FN46],[FN50], it is reported that one subject received an overdose of sodium phosphate while the other subjects took a split-dose regimen of 90-mL.

FN43. Markowitz GS, Nasr SH, Klein P, Anderson H, Stack JI, Alterman L, Price B, Radhakrishnan J, D'Agati VD. Renal failure due to acute nephrocalcinosis following oral sodium phosphate bowel cleansing. Hum Pathol 2004:35:675-84

FN45. Markowitz GS, Stokes MB, Radhakrishnan J, D'Agati VD. Acute phosphate nephropathy following oral sodium phosphate bowel purgative: an underrecognized cause of chronic renal failure. J Am Soc Nephrol 2005;16:3389-96

FN46. Gonlusen G, Akgun H, Ertan A, Olivero J, Truong LD. Renal failure and nephrocalcinosis associated with oral sodium phosphate bowel cleansing: clinical patterns and renal biopsy findings, Arch Pathol Lab Med 2006;130:101-6

FN50. Aaseb?? W, Scott H, Ganss R. Kidney biopsies taken before and after oral sodium phosphate bowel cleansing. Nephrol Dial Transplant 2007:22:920-922

Markowitz, et al have hypothesized that age, hypertension, atherosclerotic vascular disease, hydration, and concomitant use of ACE-Is, ARBs, diuretics, or non-steroidal antlinflamatory drugs (NSAIDs) might increase the risk of acute phosphate nephropathy.[FN43],[FN45] The mean age of the subjects reported by Markowitz, et al was 64 years old (range 39-82), with 18/21 (85.7%) over the age of 51. In all, 16/21 (76.2%) subjects had hypertension, and 14 of these subjects were using either an ACE-i or an ARB. Four of the subjects were using a diuretic and three were using an NSAID. Coronary artery disease was present in four (19%) subjects. A gender predominance was also noted, with 17 (80.9%) of the subjects being female. Information on hydration provided during the bowel preparation is lacking. In five cases with more detailed histories,[FN43] the subjects were reported to have received between 0 and 36 ounces of additional liquid with the bowel preparation, which is inadequate according to published[FN35] and manufacturer's[FN26],[FN27] recommendations. The remaining published cases provide no additional information on hydration. Finally, although all but one subject developing phosphate nephropathy associated with sodium phosphate solution reportedly took a standard total preparation volume (90 mL), exact dosing intervals are not provided in the published reports.

FN26. Physician's Desk Reference, 52nd ed. Montvale, NJ: Medical Economics Data; 1998:996

FN27. Physician's Desk Reference, 60th ed. Montvale, NJ: Medical Economics Data:2006:1170-2

FN35. Hookey LC, Depew WT, Vanner S. The safety profile of oral sodium phosphate for colonic cleansing before colonoscopy in adults, Gastrointest Endosc 2002:56:895-902

FN43. Markowitz GS, Nasr SH, Klein P, Anderson H, Stack JI, Alterman L, Price B, Radhakrishnan J, D'Agati VD. Renal failure due to acute nephrocalcinosis following oral sodium phosphate bowel cleansing. Hum Pathol 2004:35:675-84

FN45. Markowitz GS, Stokes MB, Radhakrishnan J, D'Agati VD. Acute phosphate nephropathy following oral sodium phosphate bowel purgative: an underrecognized cause of chronic renal failure. J Am Soc Nephrol 2005;16:3389-96

The conclusions of Markowitz, et al are based on observations made within their study cohort and have not been compared to a control population. Their larger case series[FN45] identified 31 total cases of acute phosphate nephropathy in an archive of 7,349 naive renal biopsies over a 5-year period from 2000-2004. However, the authors excluded nearly one-third of these subjects (10/31) due to superimposed renal findings that could account for acute renal failure (4), no history of colonoscopy (2), hypercalcemia (2), and lack of recall about which bowel preparation had been used before a colonoscopy (2). Among these excluded subjects, four subjects had confirmed sodium phosphate exposure, although the details of their medical histories are not provided. It would be inappropriate to make any definitive conclusions about specific risk factors associated with nephrocalcinosis and renal failure following sodium phosphate bowel preparation without an appropriate control population and further study. Furthermore, the true incidence rate of this disorder remains largely unknown from this observational case series,[FN51],[FN52] though it is thought to be rare.[FN43],[FN45],[FN46]

FN43. Markowitz GS, Nasr SH, Klein P, Anderson H, Stack JI, Alterman L, Price B, Radhakrishnan J, D'Agati VD. Renal failure due to acute nephrocalcinosis following oral sodium phosphate bowel cleansing. Hum Pathol 2004:35:675-84

FN45. Markowitz GS, Stokes MB, Radhakrishnan J, D'Agati VD. Acute phosphate nephropathy following oral sodium phosphate bowel purgative: an underrecognized cause of chronic renal failure. J Am Soc Nephrol 2005;16:3389-96

FN46. Gonlusen G, Akgun H, Ertan A, Olivero J, Truong LD. Renal failure and nephrocalcinosis associated with oral sodium phosphate bowel cleansing: clinical patterns and renal biopsy findings, Arch Pathol Lab Med 2006;130:101-6

FN51. Koretz RL. The devil is in the denominator. Gastroenterology 2006:130:2240-2

FN52. Markowitz GS, Stokes MB, Radhakrishnan J, D'Agati VD. The devil is in the denominator (reply). Gastroenterology 2006:130:2242

Subsequent Clinical Investigation of the Renal Effects of Bowel Preparation

Several clinical studies have been published recently characterizing the incidence of and risk factors for electrolyte abnormalities and renal injury following bowel cleansing for colonoscopy. Ainley et al[FN53] studied 100 consecutive patients undergoing outpatient colonoscopy and found that 45% of subjects had elevated serum phosphorous at the time of colonoscopy, which was positively correlated with creatinine, age, and the use of concomitant ACE-inhibitors, ARBs, or diuretics. However, the findings of this study were hampered by the fact that subjects took their second dose of sodium phosphate at varying intervals prior to the colonoscopy, limiting any conclusions that can be made about the prevalence of electrolyte abnormalities after sodium phosphate preparation. No subjects in this study suffered an adverse event related to bowel preparation.

FN53. Ainley EJ, Winwood PJ, Begley JP. Measurement of serum electrolytes and phosphate after sodium phosphate colonoscopy bowel preparation: an evaluation. Dig Dis Sci 2005:50:1319-23

In a retrospective database study, Vanner and colleagues reviewed the records of 767 patients with normal baseline creatinine who had undergone paired colonoscopy exams between one and five years apart.[FN54] The incidence of renal insufficiency was compared among subjects receiving sodium phosphate (n = 618) or PEG-ELS (n = 149) for their initial exam. Baseline creatinine clearance was similar in both groups, and the magnitude of change in creatinine at follow-up colonoscopy did not differ between the groups. Overall, 7% of subjects developed an abnormal creatinine or calculated creatinine clearance during the study period, including 42/618 (6.8%) sodium phosphate subjects and 13/149 (8.7%) PEG-ELS subjects (p = NS). Logistic regression analysis demonstrated that only age (p=0.014) and blood pressure (p=0.001) were predictive of the development of renal failure but not bowel preparation used.

FN54. Abaskharoun R, Depew W, Vanner S. Changes in renal function following administration of oral sodium phosphate or polyethylene glycol for colon cleansing before colonoscopy. Can J Gastroenterol, 2007 Apr;21:227-31

We participated in a multicenter study examining the longitudinal effects of sodium phosphate on renal function and electrolytes in subjects undergoing elective colonoscopy with sodium phosphate bowel preparation.[FN55] Participants were recruited into two groups: those on no medications implicated in phosphate nephropathy (Group I) and those who were using an ACE-inhibitor, ARB, and/or diuretic (Group II). A standard, divided 90-mL sodium phosphate regimen was prescribed with a 10-hour dosing interval and 72-ounces of fluid rehydration. Subjects took their second dose of sodium phosphate approximately 3-4 hours prior to their colonoscopy. Metabolic parameters were measured at baseline, on the date of the colonoscopy exam, and serially at 2, 30, and 90 days after the exam. A total of 180 subjects completed the protocol. Comparing both groups, there were no differences in changes seen in serum phosphorous, serum calcium, or serum and urine osmolality between baseline and the exam. Mean serum and urine osmolality fell similarly in both groups from baseline to exam, indicating preservation of volume status. Calculated glomerular filtration rate (GFR) improved slightly for both groups on the date of exam (Group I:p = 0.03, Group II p = 0.04) and was unchanged at the 2-day and 30-day measurements compared to baseline. In Group I, there was a clinically insignificant fall in GFR between screening and day 90 (GFR change -2.9 mL/min); no statistical change in GFR was seen in Group II. Among 22 subjects with low baseline GFR (< 60 mL/min), the mean GFR increased from 54.6 ± 4.9 at baseline to 57.8 ± 8.4 at 90 days; 11 subjects demonstrated an Increased GFR, 8 were unchanged, and 3 declined. In summary, sodium phosphate was not associated with a predictable decline in renal function in subjects with normal baseline renal function or in those with moderate chronic kidney disease. Furthermore, the use of concomitant ACE-inhibitors, ARBs, or diuretics had no effect on changes in serum electrolytes, volume status, or renal function following sodium phosphate bowel preparation.

FN55. Balaban DH, Harlan WR, Beavers KL, Moe SM, Thompson WO, Pambianco DJ. Multicenter longitudinal evaluation of the renal effects of sodium phosphate bowel preparation. Am J Gastroenterol 2005;100 (s7):S353-4

Recently, three large observational, retrospective trials have been published investigating the association between kidney injury and sodium phosphate use.[FN56] ,[FN57],[FN58] Russmann, et al evaluated the risk of acute kidney injury in a cohort of 2,352 patients undergoing colonoscopy in the Henry Ford Health System in Detrolt, MI.[FN56] Comparing subjects who received sodium phosphate to those receiving PEG, the authors demonstrated no interaction between bowel preparation choice and the development of subsequent renal dysfunction in the six months following colonoscopy (adjusted relative risk = 1.14, 95% Cl 0.55-2.39). Significant factors for the development of renal dysfunction included age ?? 65 years, African-American race, low baseline glomerular filtration rate, hypertension, and use of angiotensin-converting enzyme inhibitors. Brunelli, et al evaluated the risk of kidney injury in a population of 2,237 patients undergoing routine outpatient colonoscopy within the University of Pennsylvania Health System.[FN57] They, too, found no association between renal injury and bowel preparation used (adjusted OR 0.70; 95% Cl 0.44-1.11). Finally, Hurst, et al, examined the rates of acute kidney injury after colonoscopy in a group of 9,799 Department of Defense beneficiaries.[FN58] In contrast to the prior two studies, this study demonstrated that the use of oral sodium phosphate solution was associated with an increased risk for acute kidney injury compared to use of an alternative bowel preparation (odds ratio 2.35; 95% confidence interval 1.51 to 3.66; P< 0,001). Each of these studies employed different definitions of renal dysfunction, making cross-trial comparison difficult. Further, only the Russmann trial specifically investigated each incidence of kidney injury to exclude disorders unrelated to the effects of bowel preparation. Both the Russmann and Brunelli trials also excluded subjects with abnormal baseline kidney function, which might have limited the power to detect adverse renal effects of bowel preparation in an at-risk population. Cumulatively, the results of these studies indicate that the incidence of acute kidney injury after colonoscopy is low, but further prospective studies are needed to more precisely define the incidence of this disorder.[FN59]

FN56. Russmann 8, Lamerato L, Marfatia A, Motsko SP, Pezzullo JC, Olds G, Jones JK. Risk of Impaired Renal Function After Colonoscopy: A Cohort Study in Patients Receiving Either Oral Sodium Phosphate or Polyethylene Glycol. Am J Gastroenterol 2007;102:1-9

FN57. Brunelli SM, Lewis JD, Gupta M, Latif SM, Weiner MG, Feldman HI. Risk of kidney injury following oral phosphosoda bowel preparations.J Am Soc Nephrol 18:2007:3199-205

FN58. Hurst FP, Bohen EM, Osgard EM, Oliver DK, Das NP, Gao SW, Abbott KC. Association of oral sodium phosphate purgative use with acute kidney injury. J Am Soc Nephrol 18;2007:3192-8

FN59. Markowitz GS, Radhakrishnan J, D'Agati VD. Towards the incidence of acute phosphate nephropathy. J Am Soc Nephrol. 2007:18:3020-2

Fleet Advisory Panels

In the wake of the reports of renal injury following sodium phosphate bowel preparation, I have served on advisory panels commissioned by C.B. Fleet. The purpose of the initial advisory panel convened in 2005 was to review the reported cases of kidney damage associated with oral sodium phosphate solution and to make recommendations to colonoscopists regarding the safe and effective use of sodium phosphate for bowel preparation. This panel met in April 2005, April 2006, October 2006, and February 2007. The panel worked independently of input from C.B. Fleet and was chaired by Douglas K. Rex, M.D. from Indiana University School of Medicine. The panel sessions have included scientific presentations from gastroenterologists, nephrologists, and a nephropathologist as well as regulatory and labeling presentations. Extensive discussion, during which all panel members contributed, culminated in the panel's report, “Oral sodium phosphate solution for bowel preparation: Literature review and recommendations of an industry-sponsored advisory panel regarding safe and effective use”. This report was distributed to U.S. gastroenterologists in April 2006. In addition, a Fleet Nephrology Advisory Panel was convened in September 2007 to focus on recent clinical and animal studies investigating the association between sodium phosphate use and kidney injury. My testimony in this action will include the facts related to the advisory panel meetings as well as their conclusions, which are set forth in published reports.

Summary

The adequacy of bowel cleansing has a direct impact on the effectiveness of colonoscopy as a diagnostic and therapeutic tool and as a screening method for colorectal polyps and cancer. Additionally, tolerability of the bowel preparation is a critical element in the acceptability of colonoscopy by patients. Sodium phosphate has been found to be superior to the other leading bowel preparation, polyethylene glycol with electrolytes, in both colon cleansing effectiveness and patient tolerability. Because of its mechanism of action, sodium phosphate is contraindicated in patients with medical conditions that increase the risk of electrolyte or volume shifts; therefore, it Is incumbent upon the clinician prescribing sodium phosphate to perform a thorough medical history as well as instruct patients on its use. It is important to emphasize hydration during sodium phosphate bowel preparation, and supplemental clear liquids should be specifically prescribed in patient instructions. When used properly in appropriate patients, sodium phosphate is a safe, well-tolerated, effective bowel cleanser for colonoscopy.

Qualifications

The opinions expressed in this report are based on my education, training, and experience as a practicing gastroenterologist and as a clinical investigator. I am board-certified in gastroenterology, and I have performed over 10,000 colonoscopy procedures in my career (approximately 1,500 per year). I use both sodium phosphate and polyethylene glycol lavage with electrolytes as bowel preparation agents in my practice. I have participated as an investigator in numerous clinical trials of bowel preparation agents (see attached CV). I have served as a paid medical consultant to Fleet Laboratories since 2002, I have received lecture fees and grant support for clinical research, and I have assisted in the development of educational materials for Fleet.

Payment

My standard hourly rate for time spent in the preparation of this report is $300/hour. Should I be asked to testify, I will be paid my standard rate of $4,000/day.