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Physicians should be aware of recent FDA drug alerts for antiinfective agents
During the past several weeks, there have been two health alerts issued by the FDA regarding the safe use of antiinfective agents. In each case, these alerts led to some confusion among health care professionals. A description of these warnings and some of the details behind the alerts are outlined below.
Aerosolized colistimethate sodium
On June 28, 2007, the FDA issued a public health advisory regarding the use of inhaled colistimethate and its possible association with the death of a patient. Although absorption of colistimethate is minimal when administered via this route, the patient developed multi-organ failure and ultimately died from what appeared to be systemic colistin toxicity.
What had occurred in this patient who was prescribed a therapy that, although not FDA–approved for administration by this route, is routinely used in the cystic fibrosis population? The patient had been prescribed aerosolized colistimethate to be administered at home via nebulizer. The medication the patient received from the pharmacy was a premixed, ready-to-use supply of colistimethate. Within hours of the first treatment, the patient developed respiratory distress that progressed during the next several days. Nineteen days later, the patient died of multi-organ failure.
This case of pulmonary toxicity, followed by what appeared to be systemic toxicity due to colistin, is likely linked to administration of a colistin preparation with a higher than normal concentration of a more toxic formulation of the drug.
In the United States, there are two commercially available preparations of colistin: colistin sulfate and colistimethate sodium. The former is considered the more toxic preparation and is only available for oral administration as part of gastrointestinal tract decontamination regimens.
Colistimethate sodium (polymyxin E) is an inactive prodrug of colistin. It is the preparation available for IV administration. When mixed with water, colistimethate undergoes spontaneous hydrolysis to two distinct forms of the active drug colistin (polymyxin E1 and polymyxin E2). One of these products, polymixin E1, is toxic to lung tissue and can actually cause sufficient damage to allow increased systemic absorption of the active drug form. This appears to be what occurred in the patient cited in the FDA advisory.
Why was this particular patient exposed to higher than normal concentrations of polymixin E1? Unlike many initially feared, this was not a case of contaminated pharmacy compounding, as has occurred in recent years with steroids and other injectible products. This is actually a normally occurring process and would be expected when colistimethate is prepared more than 24 hours prior to its intended use. At most inpatient treatment facilities, it is protocol to discard any unused colistimethate within 24 hours of admixture.
When used in the outpatient setting, premixing the medication is a convenient option for many patients. However, this practice results in a more toxic preparation given to patients. For any clinician who is using aerosolized colistin in the outpatient setting, it is important to ensure that the medication supply is not being compounded in advance.
The FDA advisory statement offers the following advice for health care professionals:
- Health care professionals using aerosolized colistimethate need to be aware of the potential toxicity arising from the polymyxin E1 metabolite.
- To avoid this toxicity, colistimethate should be administered promptly after being mixed.
- Patients should be advised not to use premixed, ready-to-use formulation of colistimethate. Also, any vials they have already purchased should be discarded.
This case serves as a careful reminder that as aerosolization of antimicrobials becomes more common in clinical practice, we must carefully monitor the safety of the agents being used.
Coadministration of ceftriaxone, calcium
On July 5, 2007, the FDA issued a warning via the MedWatch alert system regarding toxicity associated with co-administration of IV ceftriaxone (Rocephin, Roche) and calcium-containing products. The letter, written by Roche representatives, outlines changes to the prescribing information for ceftriaxone in regards to calcium products. In the warning section, the following statements were added:
- Ceftriaxone must not be mixed or administered simultaneously with calcium-containing solutions or products, even via different infusion lines.
- Calcium-containing solutions or products must not be administered within 48 hours of last administration of ceftriaxone.
- Cases of fatal reactions with calcium-ceftriaxone precipitates in lungs and kidneys in both term and preterm neonates have been described. In some cases, the infusion lines and times of administration of ceftriaxone and calcium-containing solutions differed.
These changes were prompted following five neonatal deaths during the past decade related to calcium-ceftriaxone precipitates in the lungs and kidneys of affected patients.
This alert led to many questions by practitioners regarding exactly which formulations of calcium were involved. Given the high frequency with which ceftriaxone is administered, particularly during respiratory infection season, the inability to administer any calcium within 48 hours of ceftriaxone presented a logistical difficulty in many institutions.
Further clarification was provided by Roche in a letter dated July 12, 2007. This letter clarifies many important considerations regarding the risk for this event. First and foremost is the patient population affected. All of the patients were neonates. There does not appear to be any similar risk observed in adult patients receiving ceftriaxone. The risk appears to be highest for neonatal patients with hyperbilirubinemia.
The letter also provides clarification for the 48-hour period of risk for administration of calcium-containing products. Although the revised prescribing information identifies all calcium-containing products and specifically states that the reaction is noted with differing administration routes, the reaction has not been reported in association with oral preparations of calcium.
In summary, use of ceftriaxone and concomitant calcium-containing products in the neonatal population is certainly a patient-safety concern. There are not, however, similar problems when calcium is administered to an adult patient receiving ceftriaxone therapy. Calcium and calcium-containing solutions should not be used as a diluent or co-infused with ceftriaxone for injection.
For more information:
- Elizabeth Dodds Ashley, PharmD, MHS, is an Associate in Research/Clinical Pharmacist at the Duke University Medical Center Division of Infectious Diseases.
- The updated letter released by Roche can be found at www.ashp.org/s_ashp/article_news.asp?CID=167&DID=2024&id=21101.
- Further details of the FDA report for health care professionals, as well as information for patients, can be found at www.fda.gov/cder/drug/infopage/colistimethate/default.htm.