Oral sodium phosphates (OSP) and renal toxicity

HSA would like to update healthcare professionals on recent overseas reports of serious adverse events of acute kidney injury associated with the use of oral sodium phosphates (OSP). OSP are indicated for relief of occasional constipation or for preparing the bowel for medical procedures. While there are no major safety concerns when used as laxatives, their use for bowel cleansing (at higher doses) have been associated with serious adverse effects such as acute phosphate nephropathy.

Locally, OSP are available over-the-counter as General Sales List (GSL) products. Examples of OSP that are available in Singapore are Fleet Phospho-Soda® Buffered Saline Laxative,Fleet Phospho-Soda® Oral Saline Laxative Ginger-Lemon and Phosphates Solution®.

Reports received by US FDA

On 11 December 2008, the US Food and Drug Administration (FDA) reported having received 20 cases of kidney injury associated with the use of OsmoPrep®, a product containing OSP available only on prescription in the United States. Three of these patients were biopsy-proven cases of acute phosphate nephropathy. Concomitant use of an ACE inhibitor or angiotensin receptor blocker was noted in 11 cases, diuretic use in six cases, NSAID use in four cases, and one patient received a contrast dye. The onset of kidney injury in these reports were varied, in some cases occurring within several hours of use of these products and in other cases up to 21 days after their use.

Reports received by Health Canada

Health Canada (HC) has also received 53 adverse reaction reports in association with OSP, of which 30 case reports involved kidney dysfunction including 27 reported as serious. Other adverse reactions included gastrointestinal symptoms, cardiovascular and neurological problems and allergic reactions.

Acute phosphate nephropathy

Acute phosphate nephropathy is the result of the formation of calcium-phosphate crystals depositing in the renal tubules. It is a rare and serious adverse event that has been associated with the use of OSP. This form of acute kidney injury may lead to permanent renal function impairment.

The risk factors associated with the development of acute phosphate nephropathy include

• Age (especially individuals over 55 years)

• A decreased intravascular volume (due to conditions such as congestive heart failure, cirrhosis, or nephrotic syndrome)

• Having baseline kidney disease (acute or chronic), bowel obstruction or active colitis

• Concomitant use of drugs that affect renal perfusion or function (such as diuretics, ACE inhibitors, angiotensin receptor blockers, and possibly NSAIDs).

Regulatory Actions

a) US FDA

As a precaution, the FDA is recommending that OSP prescription products be used with caution for bowel cleansing by individuals with the risk factors mentioned above. Additionally, FDA has strengthened the labeling of two prescription products, Visicol® and Osmoprep®. The manufacturers of these products are also required to include a medication guide and conduct post marketing studies to assess the risk of kidney injuries with their respective products. The current available data on over-the-counter OSP (e.g. Fleet Phospho-Soda®) do not show a risk of acute kidney injury when they are used at doses for laxative purposes, which are lower than doses for bowel cleansing. However, the use of over-the-counter OSP for the purpose of bowel cleansing (at higher doses) will have the same risks as prescription OSP.FDA plans to amend the labelling conditions for over-the-counter OSP to address this concern. FDA is recommending that over-the-counter OSP not be used for bowel cleansing. Consumers were advised to only use OSP for bowel cleansing pursuant to a prescription from a healthcare professional.

b) Health Canada (HC)

An advisory was issued by HC on 5 Mar 2009 stating that although these products have a long history of safe use as laxatives, they have been associated with serious adverse effects, including electrolyte disturbances and kidney injury, when used as bowel cleansers. The instructions for purgative use on the labels of these products should no longer be followed, unless recommended by a health care practitioner. HC is working with companies marketing OSP products to update the labeling of the affected products.

Local Situation

The locally registered OSP already carry warnings against use in kidney disease and caution against use except under medical supervision/advice. Nevertheless, IDS Pharmaceutical Division had taken a precautionary measure to voluntarily recall their OSP product, i.e. Phosphates Solution® on 4 March 2009 although all stocks of Phosphates Solution® are not labeled for bowel cleansing.

In a further step to minimize risk to consumers and ensure the appropriate use of OSP products, HSA published a consumer advisory on HSA website recently to advise consumers to seek medical advice before using these products for bowel cleansing.

To date, HSA has not received any local reports of acute phosphate nephropathy associated with OSP. Nevertheless, healthcare professionals are advised to take into consideration this recent safety finding on OSP when prescribing them to patients. It is recommended that OSP be used with caution in patients who are at risk of developing acute phosphate nephropathy.

References

1. FDA Alert [12/11/2008]http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm103354.htm

2. Health Canada Public Warning [5 March 2009]. http://www.healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2009/13368a-eng.php