The agency mandates labeling and testing for aluminum-containing products used for total parenteral nutrition therapy.
Evidence has surfaced that links the use of parenteral drug products containing aluminum to increased mortality of patients on total parenteral nutrition (TPN) therapy, especially among premature babies and patients with kidney problems.
Therefore, FDA has added several requirements for large-volume parenterals (LVPs), small-volume parenterals (SVPs), and pharmacy bulk packages (PBPs) that contain aluminum and are used for TPN therapy.
In a final rule published in the January 26, 2000, Federal Register [65 FR:4103–4111], the agency mandates certain labeling requirements for such products, restricts the amount of aluminum allowed in LVPs, and requires applicants to submit FDA-validated assay methods for determining aluminum content in parenterals.
The rule takes effect January 26, 2001, and label changes must be in place by that time.
When drugs are administered orally, the gastrointestinal tract prevents aluminum from being absorbed into a patient's tissues. However, when drugs are administered parenterally, aluminum can be deposited in tissues, potentially at toxic amounts. Premature babies and patients with impaired kidney function were the two groups in which research showed the greatest link between absorbed aluminum and death.
Consequently, all LVPs used for TPN will no longer be allowed to have more than 25 µg/L of aluminum. This includes parenteral amino acid solutions, parenteral lipid emulsions, saline and electrolyte solutions, highly concentrated dextrose solutions, and sterile water for injection. In addition, the "Precautions" section of the labeling of these LVPs must state that the aluminum limit is not exceeded.
For SVPs and PBPs, the maximum level of aluminum at expiry must be noted on the immediate container label, using the phrase, "Contains no more than (number) µg/L of aluminum." For lyophilized powders, the wording must read, "When reconstituted in accordance with the package insert instructions, the concentration of aluminum will be no more than (number) µg/L."
The maximum level is defined as the highest of the following three levels: the highest level found in batches produced in the last three years; the highest level found in the latest five batches; or the maximum historical level, but only until the first five batches after January 26, 2001, are completed.
In addition, a warning statement for all TPN packages containing aluminum must be included in the "Warnings" section of the package insert. It should read as follows:
WARNING: This product contains aluminum that may be toxic. Aluminum may reach toxic levels with prolonged parenteral administration if kidney function is impaired. Premature neonates are particularly at risk because their kidneys are immature, and they require large amounts of calcium and phosphate solutions, which contain aluminum.
Research indicates that patients with impaired kidney function, including premature neonates, who receive parenteral levels of aluminum at greater than 4 to 5 µg/kg/ day accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue loading may occur at even lower rates of administration.
Finally, applicants and manufacturers are required to use validated assay methods to show how much aluminum is contained in each parenteral package for TPN therapy. The methods must comply with the good manufacturing practices listed in 21 CFR 211.194(a). Firms that hold approved applications for any parenterals used in TPN therapy must, in accordance with 21 CFR 314.70(c), submit a supplement to FDA describing their assay methods. Applications in progress and in the future must include the validation method used and the release data for several batches. Assay methodology for parenteral products not subject to approved applications must be made available to FDA during inspections.
The agency estimates that total annualized compliance will cost about $23.8 million, which accounts for $13.2 million in recurring annual costs and up-front costs of $67.3 million to be spread out at $10.6 million per year. This figure is higher than the agency's original estimate because it underestimated compliance costs for label changes, among other reasons.
For further information, contact Leanne Cusumano, Center for Drug Evaluation and Research (HFD-7), FDA, 5600 Fishers Ln., Rockville, MD 20857; 301/594-2041.