LETTERS TO THE EDITOR

Re: Balaban et al.—Low VolumeBowel Preparation for Colonoscopy:Randomized Endoscopist-Blinded Trialof Liquid Sodium Phosphate VersusTablet Sodium Phosphate

TO THE EDITOR: In their recent article, Balaban et al. (1)conclude that liquid sodium phosphate (Fleet Phosph-Soda,C.B. Fleet, Lynchburg, VA) is better tolerated and moreeffective at colon cleansing than sodium phosphate tablets(Visicol, InKine Pharmaceutical, Blue Bell, PA). We atInKine believe that this study, which was performed at asingle center and supported by C.B. Fleet, might have hadseveral serious methodologic flaws and that the report has acritical factual omission.

First, the article indicates that 23.2% of the patientsscreened for the study declined to participate because of “arequest not to take the tablets.” This number is grosslyinconsistent with the roughly 3% of patients who havedeclined a tablet colon preparation in our studies (unpub-lished data). The fact that so many subjects rejected a tabletpreparation out of hand in the Balaban study strongly sug-gests that this therapeutic option was presented to studypatients in a negatively biased manner, which would tend todistort and invalidate the subsequent testing of patient atti-tudes about the preparation.

Similar bias against the tablet is suggested by the virtuallyidentical mean scores of the Likert scale for taste (3.0 �0.75 for the liquid vs 3.0 � 0.62 for the tablets). This scaleranged from 1 to 5, for “very poor” to “very good,” respec-tively. In our studies, 71% of patients found that Visicol (ahard, tightly compressed tablet) was tasteless (unpublisheddata). The very salty taste of the Fleet product is difficult tomask with any beverage. It is unexpected that study patientswould rate a virtually tasteless tablet (taken with any clearliquid) to be equivalent in taste to a sodium phosphatesolution. The data for taste suggest that most patients in bothstudy groups rated the taste of the preparation as “3”;perhaps the wording of the scale encouraged this result–fewwould rate any preparation as tasting “good” or “verygood.”

The authors state that seizures have been reported withsodium phosphate tablets but not with the liquid, citing apublished report by U.S. Food and Drug Administration(FDA) authors and an online FDA “Science Backgrounder.”However, another FDA “Science Backgrounder” (dated July27, 2002) that is not cited by the authors indicates that liquidsodium phosphate has been associated with seizures in pub-lished reports (2). PEG colon preparations have likewisebeen associated with seizures and fatalities (3).

Finally, the article indicates that this study was performedwith the original formulation of Visicol tablets, which con-tained the common, insoluble tablet binder microcrystallinecellulose (MCC). MCC might be visible during colonos-copy, requiring suctioning. Unlike stool, MCC is generallyeasy to suction. It appears that MCC contributed to thegrading of “stool” in the colons of patients taking the tablets,because there was no other way to rate MCC in the instru-ment used in this study. The article correctly states that thecurrently marketed formulation of Visicol contains lessMCC than the original one; in fact, it contains less than onehalf the amount of MCC in the formulation used in theBalaban study. Also, data published by Rex et al. indicatethat a reduced tablet regimen (28 or 32 old formulationtablets, compared with the 40-tablet regimen used by Bala-ban) produces very good colon cleansing and that fewertablets are associated with less visible MCC (4). Notably,the old formulation of Visicol at a dose of 40 tablets wasequivalent to the leading PEG preparation in colon cleans-ing and was much better tolerated in two identical, random-ized, investigator-blinded, multicenter studies involving 845patients undergoing colonoscopy (5). We believe that thecurrent formulation of Visicol, with less MCC, results ineven better colon cleansing than the old formulation.

Martin Rose, M.D., J.D.InKine Pharmaceutical Company

Blue Bell, Pennsylvania

REFERENCES

1. Balaban DH, Leavell BS, Oblinger MJ, et al. Low volumebowel preparation for colonoscopy: Randomized endoscopist-blinded trial of liquid sodium phosphate versus tablet sodiumphosphate. Am J Gastroenterol 2003;98:8277–32.

2. US Food and Drug Administration, Center for Drug Evaluationand Review. Science backgrounder: Seizure associated with theuse of Visicol for colonoscopy—additional information, 2002.Available at: http://www.fda.gov/cder/drug/safety/visicol.htm.Accessed May 28, 2003.

3. Ayus JC, Levine R, Arieff AI. Fatal dysnatraemia caused byelective colonoscopy. BMJ 2003;326:382–4.

4. Rex DK, Chasen R, Pochapin MB. Safety and efficacy of tworeduced dosing regimens of sodium phosphate tablets for prep-aration prior to colonoscopy. Aliment Pharamcol Ther 2002;16:937–44.

5. Kastenberg D, Chasen R, Choudhary C, et al. Efficacy andsafety of sodium phosphate tablets compared with PEG solutionin colon cleansing: Two identically designed, randomized, con-trolled, parallel group, multicenter phase III trials. GastrointestEndosc 2001;54:705–13.

THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 98, No. 10, 2003© 2003 by Am. Coll. of Gastroenterology ISSN 0002-9270/03/$30.00Published by Elsevier Inc.

Reprint requests and correspondence: Martin Rose, M.D., In-Kine Pharmaceutical Company, Inc., 1787 Sentry Parkway West,Building 18, Suite 440, Blue Bell, PA 19422.

Received June 2, 2003; accepted July 8, 2003.

Response to Dr. RoseTO THE EDITOR: Dr. Rose raises several importantpoints. He cites unpublished data demonstrating that a muchlower percentage of subjects declined to take a tablet prep-aration for colon cleansing in a study performed at InKinethan in our study. Although we cannot attest to the compa-rability of these unpublished observations, subjects in ourstudy received unbiased descriptions of both treatment armsbefore enrollment. The inclusion of only those subjects whoexpressed an a priori willingness to take a tablet preparationshould bias the results in favor of the tablet group. Inactuality, our results showed that subjects in the liquidsodium phosphate group reported superior acceptability andgreater willingness to repeat the preparation in the futurethan did subjects in the tablet group.

Dr. Rose points out that taste was ranked equally in bothgroups. Indeed, 66.7% of liquid subjects and 74% of tabletsubjects recorded the taste of their preparation as “Okay”(score � 3 on a 5-point scale). We agree that it would bechallenging to manufacture a “good” tasting colon prepara-tion; our results reflect that. The data do show, however, thatthe salty taste of liquid sodium phosphate can be maskedeffectively by diluting the product in a cold clear beverage(i.e., ginger ale). Although Visicol is marketed as tasteless,we found that many subjects in the tablet arm reported thatthe tablets were “salty.” We have observed that the tablet’scoating dissolves if it is not swallowed quickly; this mightexplain the 29% of subjects who report that the tablet is nottasteless (InKine data).

Dr. Rose characterizes a recent U.S. Food and DrugAdministration publication (1) on the safety of sodiumphosphate preparations as a “critical factual omission” fromour article. In fact, this report was issued after the submis-sion of our manuscript on June 4, 2002. The report describesfive cases of seizure associated with Visicol. In addition, thereport refers to three published cases of seizure associatedwith “over-the-counter sodium phosphate-containing prep-arations.” However, all of these cases occurred after theadministration of sodium phosphate in enema form (2, 3, 4).Two of the cases involved infants 6 weeks (2) and 9 months(3) of age, in whom sodium phosphate is contraindicated. Asstated in our article, we are aware of no reports of seizureassociated with sodium phosphate oral solution for colonpreparation. When administered in the recommended dosingregimen to adults without known medical contraindicationsto the product (e.g., renal failure, congestive heart failure,ascites, or bowel obstruction), liquid sodium phosphate issafe for oral administration before colonoscopy (5).

Finally, we note in our article that Visicol has beenreformulated with less microcrystalline cellulose (MCC).We have recently completed a study of this reformulatedtablet compared with liquid sodium phosphate for colonos-copy preparation (6). We found that 90.7% of subjectstaking the liquid preparation achieved “excellent” or “good”colon cleansing versus 76.0% taking the standard 40-tabletVisicol dose and 82.2% taking a low-dose, 28-tablet regi-men (Mantel-Haenszel p � 0.05 across groups). MCC wasseparately recorded, and our results corroborate those ofRex et al. (7) by demonstrating less residual MCC in the28-tablet group than in the 40-tablet group (p � 0.03).Despite the tablet reformulation, however, subjects takingthe liquid formulation still ranked their preparation as easierto swallow (p � 0.0003) and more convenient to take (p �0.0002) than either of the tablet regimens.

We believe that our data consistently support the use ofliquid sodium phosphate as the preparation of choicewhen selecting a low-volume colon cleansing agent forcolonosocopy.

David H. Balaban, M.D.Daniel J. Pambianco, M.D., F.A.C.G.

Charlottesville Gastroenterology Associates andCharlottesville Medical Research

Charlottesville, Virginia

William O. Thompson, Ph.D.Medical College of Georgia

Augusta, Georgia

REFERENCES

1. U.S. Food and Drug Administration, Center for Drug Evalua-tion and Research. Science backgrounder: Seizure associatedwith the use of Visicol for colonoscopy—additional informa-tion. Available at: http://www.fda.gov/cder/drug/safety/visi-col.htm. Accessed June 18, 2003.

2. Walton DM, Thomas DC, Aly HZ, et al. Morbid hypocalcemiaassociated with phosphate enema in a six-week-old infant.Pediatrics 2000;106:E37.

3. Loughnan P, Mullins GC. Brain damage following a hypertonicphosphate enema. Am J Dis Child 1977;131:1032.

4. Martinez R. Report of a case. JAMA 1987;258:782–3 (letter).5. Hookey LC, Depew WT, Vanner S. The safety profile of oral

sodium phosphate for colonic cleansing before colonoscopy inadults. Gastrointest Endosc 2002;56:895–902.

6. Balaban DH, Leavell BS Jr, Oblinger MJ, et al. Randomizedendoscopist-blinded trial of liquid sodium phosphate vs. twodosing regimens of tablet sodium phosphate. Gastrointest En-dosc 2003;57:AB102 (abstract).

7. Rex DK, Chasen R, Pochapin MB. Safety and efficacy of tworeduced dosing regimens of sodium phosphate tablets for prep-aration prior to colonoscopy. Aliment Pharamcol Ther 2002;16:937–4.

Reprint requests and correspondence: David H. Balaban, M.D.,Charlottesville Gastroenterology Associates, 1139 East HighStreet, Suite 203, Charlottesville, VA 22902.

Received June 24, 2003; accepted July 8, 2003.

2329AJG – October, 2003 Letters to the Editor