Information for Healthcare Professionals: Oral Sodium Phosphate (OSP) Products for Bowel Cleansing (marketed as Visicol and OsmoPrep, and oral sodium phosphate products available without a prescription)
FDA ALERT [12/11/2008]: FDA has become aware of reports of acute phosphate nephropathy, a type of acute kidney injury, associated with the use of oral sodium phosphate products (OSP) for bowel cleansing prior to colonoscopy or other procedures. These products include the prescription products, Visicol and OsmoPrep, and OSPs available over-the-counter without a prescription as laxatives (e.g., Fleet Phospho-soda). In some cases when used for bowel cleansing, these serious adverse events have occurred in patients without identifiable factors that would put them at risk for developing acute kidney injury. We cannot rule out, however, that some of these patients were dehydrated prior to ingestion of OSPs or they did not drink sufficient fluids after ingesting OSP.
Acute phosphate nephropathy is a form of acute kidney injury that is associated with deposits of calcium-phosphate crystals in the renal tubules that may result in permanent renal function impairment. Acute phosphate nephropathy is a rare, serious adverse event that has been associated with the use of OSPs. The occurrence of these events was previously described in an Information for Healthcare Professionals sheet and an FDA Science Paper issued in May 2006. Additional cases of acute phosphate nephropathy have been reported to FDA and described in the literature since these were issued.
Individuals who appear to have an increased risk of acute phosphate nephropathy following the use of OSPs include persons: who are over age 55; who are hypovolemic or have decreased intravascular volume; who have baseline kidney disease, bowel obstruction, or active colitis; and who are using medications that affect renal perfusion or function (such as diuretics, angiotensin converting enzyme [ACE] inhibitors, angiotensin receptor blockers [ARBs], and possibly nonsteroidal anti-inflammatory drugs [NSAIDs]).
As a result of new safety information received, FDA is requiring the manufacturer of Visicol and OsmoPrep, the two OSPs available by prescription only, to add a Boxed Warning to the labeling for these products. FDA is also requiring that the manufacturer develop and implement a risk evaluation and mitigation strategy (REMS), which will include a Medication Guide, to ensure that the benefits of these products outweigh the risk of acute phosphate nephropathy, and to conduct a postmarketing clinical trial to further assess the risk of acute kidney injury with use of these products.
FDA acknowledges that OSP products, in addition to use for bowel preparation, have a long history of safe use as non-prescription products as laxatives (i.e. for relief of constipation) and accordingly, they will continue to be available over-the-counter for this use. However, in light of the risk of acute phosphate nephropathy, over-the-counter laxative OSP products should not be used for bowel cleansing. Consumers should only use OSPs for bowel cleansing pursuant to a prescription from a healthcare professional. FDA intends to amend the labeling conditions for OSP products available in the OTC setting to address this concern with bowel cleansing use and to improve the safe use of OSPs that are available over-the counter. FDA’s amendment to remove the professional labeling for bowel cleansing for these OSPs available over-the-counter will be published in a future Federal Register notice.
This information reflects FDA’s current analysis of data available to FDA concerning these drugs. FDA intends to update this sheet when additional information or analyses become available.
To report any unexpected adverse or serious events associated with the use of these drugs, please contact the FDA MedWatch program either online, by regular mail or by fax, using the contact information at the bottom of this sheet.
Information for healthcare professionals to consider when ordering an OSP bowel preparation for their patients:
Acute phosphate nephropathy presents as acute kidney injury with minimal proteinuria and a bland urine sediment in patients recently exposed to OSP. Renal biopsy typically reveals acute and/or chronic renal tubular injury (depending on time to diagnosis), calcium-phosphate crystal deposition in the distal tubules and collecting ducts, and no other pattern of histological injury.
When prescribing OSPs for bowel preparation, healthcare professionals should consider the following points:
- Provide easy to understand instructions to the patient about how to prepare for the procedure, and tell them what symptoms to be aware of in order to help them recognize, and possibly mitigate the risk of acute kidney injury.
- Instruct patients of the need to drink sufficient quantities of clear fluids before, during and after bowel cleansing. There are publications suggesting that use of an electrolyte or carbohydrate-electrolyte replacement solution may help decrease the electrolyte abnormalities and hypovolemia associated with OSP bowel cleansing.
- Avoid exceeding the maximum recommended OSP doses.
- Avoid concomitant use of laxatives containing sodium phosphate.
- Avoid use of OSPs in children under 18 years of age.
- Use OSPs with caution in patients over 55 years of age.
- Use OSPs with caution in patients with dehydration, kidney disease, delayed bowel emptying, or acute colitis.
- Use OSPs with caution in patients taking medicines that affect kidney function or perfusion, such as diuretics, angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and possibly non-steroidal anti-inflammatory drugs (NSAIDs).
- In patients who may be at increased risk for acute phosphate nephropathy, including those with vomiting and/or signs of dehydration, obtain baseline and post-procedure labs (electrolytes, calcium, phosphate, BUN and creatinine). For smaller, frail individuals, also monitor glomerular filtration rate.
- Consider hospitalization and intravenous hydration during bowel cleansing to support frail patients who may be unable to drink an appropriate volume of fluid or who may be without assistance at home.
In May 2006, FDA posted on its website an Information for Healthcare Professionals sheet and a Science Paper describing cases of acute phosphate nephropathy associated with the use of prescription and over-the-counter OSP laxatives when used for bowel cleansing. At the time of posting, there were no cases of acute phosphate nephropathy associated with OsmoPrep as it had just been approved. Since that time, FDA has continued to receive adverse event reports and there have been reports in the literature describing OSP-associated acute kidney injury.
Since May 2006, FDA has continued to receive reports of acute phosphate nephropathy with both prescription and products available in the OTC setting. Twenty unique cases of acute kidney injury associated with the use of OsmoPrep were reported to FDA’s Adverse Event Reporting System (AERS) database. The onset of the kidney injury occurred from several hours to 21 days after OSP use. Three of these patients had a kidney biopsy, the results of which revealed acute phosphate nephropathy. Concomitant use of an ACE inhibitor or angiotensin receptor blocker was noted in 11 cases, diuretic use in 6 cases, NSAID use in 4 cases, and 1 patient received a contrast dye. Five cases were reported to be life-threatening and ten resulted in hospitalization. Of these 20 cases, 4 patients required dialysis for an unspecified period of time and one patient died from complications of pneumonia. Nine patients were reported to have renal impairment that continued for at least 2 to 4 weeks; the duration of renal impairment is unknown for 7 patients.
Recently published observational, retrospective studies (see below) attempt to assess the incidence of subclinical (without symptoms) kidney injury after OSP use for bowel preparation. It is not entirely clear how the observations in these studies relate to other cases of acute phosphate nephropathy that become evident because of the development of clinical symptoms which lead physicians to conduct testing. These studies only assess changes in serum creatinine in a cohort of people who received OSP for bowel cleansing, in an attempt to determine whether lesser degrees of kidney injury occur in a population of patients receiving OSP. Brunelli et al. conducted a retrospective, case-control study of outpatients undergoing colonoscopy, comparing those who subsequently developed kidney injury, defined as a 25 percent or > 0.5 mg/deciliter increase in serum creatinine, to those who did not. The Brunelli study found no statistically significant association between acute kidney injury and exposure to OSP, but did find a significant interaction indicating increased risk for kidney injury from OSP in patients who were simultaneously receiving ARBs or ACE inhibitors. The Brunelli study also found that risk factors for the development of acute kidney injury included female gender, heart failure, and diuretic use. In addition, another observational retrospective cohort study by Hurst et al. revealed an increased risk of acute kidney injury, defined as > 50% increase in baseline serum creatinine, in patients undergoing bowel cleansing using OSP products compared to polyethylene glycol or PEG preparations. However, a recent study by Russmann et al. evaluated the risk of impaired kidney function after colonoscopy and revealed that in patients without preexisting kidney disease, the risk of renal impairment, defined as calculated glomerular filtration rate less that 60 mL/minute, after colonoscopy appears to be similar for sodium phosphate and PEG users. There are limitations in the design of all of these studies, such as the lack of a consistent definition of acute kidney injury and the exclusion of patients with baseline serum creatinine values above a threshold value. As a consequence, no definitive conclusions can be drawn and prospective studies are needed to further assess subclinical changes in kidney function.
Under its new authorities provided in the Food and Drug Administration Amendments Act of 2007, FDA is requiring the manufacturer of the two prescription OSP products, Visicol and OsmoPrep to add a Boxed Warning to the labeling for their products and to implement a risk evaluation and mitigation strategy (REMS) to ensure that the benefits of the drugs will outweigh the risk of acute phosphate nephropathy. FDA is also requiring that the manufacturer conduct a postmarketing clinical trial to further assess the risk of acute kidney injury with use of these drugs.
Since these risks are associated with all OSPs used for bowel cleansing, whether they are available by prescription or in the over-the-counter setting, FDA is also taking measures to ensure the safe use of OSPs that are available without a prescription. To accomplish the latter, FDA intends to amend the labeling conditions for OSP products available in the OTC setting to address this concern with bowel cleansing use and to improve the safe use of OSPs that are available over-the counter. FDA’s amendment to remove the professional labeling for bowel cleansing for these OSPs available over-the-counter will be published in a future Federal Register notice.
Brunelli SM, Lewis JD, Gupta M, et al. Risk of kidney injury following oral phosphosoda bowel preparations. J Am Soc Nephrol 18: 3199-3205; 2007
Hurst F, et al Association of oral sodium phosphate purgative use with acute kidney injury. J Am Soc Nephrol 18: 3192-3198 2007
Markowitz GS, Radhakrishnan J and D’Agati VD. Towards the incidence of acute phosphate nephropathy. J Am Soc Nephrol 18: 3020-3022; 2007
Russman S, Lamerata L, et al Risk of impaired renal function after colonoscopy: A cohort study in patients receiving either oral sodium phosphate or polyethylene glycol. Am J Gastroenterol 102:2655-2663; 2007
Heher EC, et al Adverse renal and metabolic effects associated with oral sodium phosphate bowel preparation. Clin J Am Soc Nephrol 3: 1494-1503; 2008