USP Quality Review

No. 70, Issued November 1999

Gentamicin: Revisions

Aminoglycosides have a narrow therapeutic range. Although a causative association is not established, high peak or high trough serum concentrations may be associated with an increased risk of nephrotoxicity and ototoxicity. There is evidence suggesting the administration of larger, less frequent aminoglycoside doses may be correlated with an improved bactericidal effect and less toxicity than the conventional multiple-dose regimen. Once-daily aminoglycoside therapy incorporates this concept into the derivation of dose and dosage interval and is currently a widely used method for aminoglycoside administration. Many hospitals and other health care facilities have adopted protocols employing once-daily aminoglycoside regimens; often the prescribed amount of gentamicin is 7mg/kg as a single daily dose1. Presently, however, this administration schedule is not included in FDA-approved labeling for aminoglycoside products.

The USP official monograph for Gentamicin Injection (USP 23, pages 703 and 4553 of the Ninth Supplement) requires that each milligram of gentamicin sulfate must not contain more than 1.70 USP Endotoxin Units. This endotoxin limit was derived from calculations with the standard and usual gentamicin dose recommended by manufacturers for adults with normal renal function; a 3mg/kg total daily dose administered in three equally divided doses at 8-hour intervals.

The USP Microbiology Subcommittee is charged with establishing and revising appropriate microbial limits, pyrogens, bacterial endotoxins, antimicrobial preservative effectiveness, and sterility requirements for USP–NF monographs and general chapters. Endotoxin limits in injections are calculated based on the approved maximum dose per kilogram per hour. When the dosage regimen of a product is changed, recalculation of the endotoxin limit is necessary. The increased reporting of endotoxin-like reactions associated with intravenous gentamicin, coupled with the recognition of current widespread gentamicin administration practices prompted the Microbiology Subcommittee to propose an endotoxin limit revision. The published proposal recently appeared in the Pharmacopeial Forum (March/April 1999; 25(2): 7832), USP's journal of standards development and official compendia revision. The proposal recommends adjusting the endotoxin specification to 0.71 USP Endotoxin Unit per mg of gentamicin. The proposal was accepted and will become official January 1, 2000, in the First Supplement to USP 24. At that time, gentamicin manufacturers will need to comply with the lower endotoxin requirement.

When products are used for a new or off-label indication, in addition to pharmacology and pharmacokinetic concerns, it is critical that practitioners consider the product's pharmaceutical properties. Revision of product specifications may be necessary for safe use of the agent. It is important to report unusual or unexpected adverse events to new indications or novel administration techniques. In doing so, a forum for drug scrutiny and revision of quality standards is created that ultimately fosters patient safety.

Reference:
1 Endotoxin-like reactions associated with intravenous gentamicin – California, 1998. MMWR.1998; 47 (41): 877-880.