On December 12, 2008, C.B. Fleet issued an immediate product recall and
directed US pharmacies to remove the over-the-counter products, Fleet
Phospho-soda and Fleet Phospho-soda EZ-Prep Bowel Cleansing System from
their shelves. These emergency measures followed an FDA safety alert stating
that oral sodium phosphate (NaP) products for use in bowel preparation
should be available by prescription only in light of the risk of acute
kidney injury.
Similar safety concerns were identified by a systematic review published in
August 2008 identifying published reports of life-threatening adverse
events, including kidney failure and death, for patients given bowel lavage
preparations. Approximately 10 million patients in Europe are prescribed
bowel lavage preparations (about 7 million PEG [polyethylene glycol]
preparations and 3 million NaP [sodium phosphate] preparations) so any
concerns over safety are extremely serious. Five times more significant
adverse events were reported for NaP when compared with PEG (109 patients
using NaP and 22 patients using PEG).
These safety issues raise potentially life threatening implications for the
thousands of healthy people currently undergoing screening as part of a
nationwide bowel cancer screening programme in the UK.
In a systematic literature review3 in Alimentary Pharmacology &
Therapeutics, Dr Jonathan Belsey and colleagues investigated the potential
safety issues associated with bowel preparation with PEG (polyethylene
glycol) and NaP (sodium phosphate) prior to bowel investigation. They found
58 publications that included significant adverse events‡ in 109 patients
using NaP and 22 patients using PEG. Electrolyte disturbances, kidney
failure and colonic ulceration were the most commonly reported adverse
events for NaP. Electrolyte disturbances, upper gastrointestinal damage and
allergic reactions were reported for PEG.
Bowel cancer affects one in 20 people in the UK and is the second most
common cause of cancer deaths, with over 16,000 people dying from it each
year.5 Regular bowel cancer screening aims to detect bowel cancer at an
early stage and has been shown to reduce the risk of dying from colon cancer
by 15%. Bowel cancer screening programmes are now high on the public agenda,
and screening will be offered every two years to all men and women aged 60
to 69 by 2009.5
Bowel preparation is crucial for any diagnostic procedure like colonoscopy
which requires good visualisation of the bowel mucosa. PEG and NaP are two
widely used preparations to cleanse the bowel. Some adverse events are often
associated with bowel preparations, such as diarrhoea, nausea and abdominal
pain, which can act as a deterrent for many of the patients undergoing
screening. The potential for serious adverse events with NaP has also been
highlighted by several drug regulatory authorities outside the US.6-8
In the cases identified in the systematic review, 25% of the patients with
metabolic disturbance died (11 of the 46 cases reported with NaP patients
died versus one of the five cases reported with PEG).
Professor Owen Epstein, Professor of Gastroenterology at the Royal Free
Hospital, and co-author of the paper commented: “In the UK, 35,000 people
are diagnosed each year with colon or rectal cancers. For this reason, bowel
screening is increasingly being used in healthy adults. However, the message
that may be unappreciated is that although clinically important
complications following the use of bowel preparations are uncommon they may
be serious. Given that many people who undergo screening are healthy, the
risks and benefits should be carefully considered by clinicians when
choosing which preparation to use.”
In 2001, the US Food and Drug Administration issued guidance relating to the
risks associated with the use of NaP. At this stage there were very few
reports for cases of kidney failure associated with calcium or phosphate
deposition in the kidney (nephrocalcinosis / acute phosphate nephropathy),
which can lead to kidney failure. However, between January 2006 and December
2007 there were 171 cases of kidney injury reported with NaP, but only 10
following the use of PEG. During the same period there were 51 cases of
phosphate nephropathy with NaP and none with PEG. These higher numbers are
likely to reflect greater awareness of the problematic safety issues
associated with NaP as a result of manufacturer warnings.
The Food and Drug Administration have required ’Black Box’ warnings
regarding the risk of acute kidney injury for two prescription NaP products
(Visicol and Osmoprep; Salix Pharmaceuticals Inc.) and that healthcare
professionals cease directing patients to use over-the-counter laxative oral
liquid NaP for bowel cleansing. In response, C. B. Fleet immediately ceased
distribution and initiated a voluntary recall of the over-the-counter NaP
products Fleet Phospho-soda and Fleet Phospho-soda EZ-Prep Bowel Cleansing
System.
The National Patient Safety Agency in the UK is also in the process of
issuing a Rapid Response Report which aims to provide safer practice
recommendations for bowel preparations.
Jonathan Belsey, Director of Health Economics at JB Medical Ltd, and lead
author of the paper commented: “All case reports of adverse events should be
taken seriously. While I strongly support early bowel screening and the use
of bowel preparations are important for this, I would urge that all
clinicians involved with screening be aware of the safety issues relating to
the different bowel preparations available.”
