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FDA Aluminum Rule Poses Challenges for Industry, Pharmacists

Donna Young

In an effort to limit patients' exposure to aluminum, beginning July 26, FDA is requiring manufacturers of large-volume parenterals (LVPs), small-volume parenterals (SVPs), and pharmacy bulk packages (PBPs) used in total parenteral nutrition (TPN) to add certain information to component products' labeling.

The agency has specified a maximum aluminum concentration of 25 mcg/L in LVPs used in TPN. FDA's regulation applies to all LVPs used in TPN, including but not limited to parenteral amino acid solutions, highly concentrated dextrose solutions, parenteral lipid emulsions, sodium chloride and electrolyte solutions, and sterile water for injection, according to FDA.

Manufacturers are required to state in the package inserts of LVPs used in TPN that the component product contains no more than 25 mcg/L of aluminum.

There is no limit for the aluminum content in SVPs and PBPs, but manufacturers are required to include in the labeling of those products the maximum level of aluminum at expiry.

The rule allows makers of SVPs and PBPs used in TPN to state in the labeling that the product "contains no more than 25 mcg/L" of aluminum, rather than declare the exact amount.

FDA is also requiring that manufacturers develop and submit for approval to the agency validated assay methods for determining the aluminum content in parenteral drug products used in TPN therapy, noted pharmacist Mary B. Baker, senior medical manager for hospital products at Abbott Laboratories.

Abbott makes numerous parenteral products used in TPN, she said, adding that her company began several years ago to comply with the requirements in anticipation of the rule's effective date and has already changed package labeling for its products.

FDA is implementing the rule because of "evidence linking the use of parenteral drug products containing aluminum to morbidity and mortality among patients on TPN therapy, especially premature neonates and patients with impaired kidney function," according to the rule.

Regulators, in 1990, first announced concerns about toxic aluminum levels in patients who receive TPN and proposed a rule in 1998 that would limit aluminum levels and require manufacturers to include certain labeling information, including a warning about potential toxicity.

The rule was to take effect in January 2001 but has been postponed three times, Baker noted.

The regulation's labeling requirements enable health care professionals administering TPN to calculate the total amount of aluminum a patient receives from multiple sources and make appropriate substitutions if the patient is in a high-risk group, according to FDA.

The agency is requiring manufacturers to include a warning in the package insert of all LVPs, SVPs, and PBPs that patients with impaired kidney function, including premature neonates, who receive more than 4-5 mcg/kg/day of aluminum by injection accumulate the metal at levels associated with central nervous system and bone toxicity.

Accumulation of aluminum in tissues may even occur from exposure to less than 4 mcg/kg/day, according to FDA.

The rule does not require pharmacists to calculate a patient's total aluminum exposure, according to Jane Axelrad, director of FDA's Office of Regulatory Policy for the Center for Drug Evaluation and Research.

The rule applies to drug manufacturers, not to pharmacists, she affirmed.

But, Axelrad added, "it could be argued that a responsible pharmacist who reads that warning and is preparing a TPN solution for a neonate or a renally impaired patient may wish to discuss any concerns about possible aluminum toxicity with the prescribing physician. But to be clear, the rule does not require the pharmacist to calculate aluminum levels."

Darryl S. Rich, associate director of surveyor management and development for the Joint Commission on Accreditation of Healthcare Organizations, said that his organization considers FDA's aluminum toxicity rule to be a requirement for pharmaceutical manufacturers and not pharmacies.

"The Joint Commission has no standards related to this issue and has no intention of changing survey process because of this new rule or to score compliance with it," Rich said.

Because pharmacists are the clinicians who typically prepare TPN formulations, they have "unique knowledge" of the process and access to information about the raw materials used in products administered to patients, said Kathleen M. Gura, central pharmacy team leader and clinical pharmacist in nutrition support for Children's Hospital in Boston, Massachusetts.

"We are going to be the ones by default who do the calculations," she declared. "The physician won't know that information about the raw materials used."

Pharmacists, Gura said, must closely monitor those patients who are at risk for aluminum toxicity.

But pharmacist Lawrence A. Trissel, director of clinical pharmaceutics research for the University of Texas M. D. Anderson Cancer Center in Houston, said not exceeding the 5-mcg/kg/day limit for a patient will be a difficult demand for pharmacists to meetif not impossible.

"Because of the amount of aluminum present in the essential components [of TPN], you just can't get it down to that level," he said. "I think the FDA, when they first proposed this [in 1998], expected that the industry would just somehow be able to make the aluminum go away, and then all these products would be very clean and without aluminum, and so all they have to do is pass this rule and everybody would go into compliance. It's not that simple."

Even if a pharmacist determines that a patient's aluminum exposure exceeds the 5-mcg/kg/day limit and notifies the physician, Trissel said, "so what, there's nothing you can do about it. The only option is to not treat the patient, not to give them the parenteral nutrition."

Pharmacists could try switching some of the components in a TPN product for ones that have a lower aluminum content, such as switching from calcium gluconate to calcium chloride, Trissel said.

But, he added, pharmacists and prescribers need to consider the clinical consequences of substituting one component for another.

To calculate the aluminum burden in a TPN solution to determine if the patient will be receiving more than 5 mcg/kg/day, clinicians should check the aluminum content of the ingredients in the product labeling and add the total aluminum in the solution and divide by the weight of the patient, said Gordon L. Klein, professor of pediatrics and preventive medicine at the University of Texas Medical Branch at Galveston.

Klein is considered an expert in aluminum toxicity research and was involved in developing FDA's rule.

FDA, Gura declared, "did a disservice" to the health care community by focusing the rule only on aluminum content in products used in TPN therapy.

Many other products, she noted, contain high levels of aluminum, such as albumin.

Products such as sucralfate, heparin, and antacids are rich in aluminum and have been linked with aluminum toxicity in patients, she added.

Glass containers and bottle stoppers have also been associated with aluminum contamination, she added.

A typical adult ingests 25 mg of aluminum with his or her food per day, Gura said.

"You can't avoid it," she said. "We eat it, we drink it. It's in 8% of the earth's crust."

But luckily, Gura said, most humans' respiratory and gastrointestinal systems are able to tolerate and eliminate the average levels of aluminum ingested daily.