To the Editor
I would like to thank you for the opportunity to respond to Dr. Urdaneta’s question, “Should We Follow These Guidelines and Recommendations or Not?” It is a valid question that has been posed many times.
As pointed out by Dr. Urdaneta, a 2006 review article published in Regional Anesthesia and Pain Medicine, stated that chlorhexidine-based solutions should be considered the antiseptic of choice for regional anesthetic procedures and that its use be considered a Grade A recommendation.1 As of 2008 all chlorhexidine-based topical cutaneous skin antiseptics have the warning “do not use for lumbar puncture or in contact with the meninges”2 or “do not use in contact with the meninges.”3
The Food and Drug Administration (FDA) approval of a drug is based on the data submitted by the manufacturer. The FDA requires that substantial evidence resulting from adequate and well-controlled investigations demonstrate that a drug will have the effect it purports or is represented to have under the conditions or use prescribed, recommended, or suggested in the proposed labeling. Once the FDA determines that a drug is safe and effective the manufacturer can only advertise or promote the drug for the indication approved by the FDA, and all promotion must be based on information that was submitted for review.4
A physician’s discretionary use of that product (the practice of medicine) is not restricted to the uses indicated on FDA-regulated labels. Off-label use is widespread in the medical community and often is essential to giving patients optimal medical care, both of which medical ethics, FDA, and most courts recognize.5 The policy statement from the American Academy of Pediatrics for Unapproved Uses of Approved Drugs states, “An unapproved use of an approved drug refers to a use that is not included or that is disclaimed in the approved labeling. Unapproved use does not imply an improper use and certainly does not imply an illegal use. The term ‘unapproved’ is used merely to indicate lack of approval, not to imply disapproval or contraindication based on evidence of a lack of safety or efficacy. The distinction between contraindication and unapproved is important medically and legally”. . . .”New uses, doses, or indications will not be approved by the FDA until substantial evidence of safety and efficacy for the indication or age group is submitted to the FDA. This may take years or may never occur.”4
Since the consensus position of the American Society of Regional Anesthesia publication in the 2006 Hebl review article stating that chlorhexidine-based solutions should be considered the antiseptic of choice for regional anesthetic procedures, there has been discordance between the evidence-based practice of many clinical providers of regional anesthesia and chlorhexidine-based antiseptic product labeling. Dr. David Hepner published a correspondence in the April 2007 issue of Anesthesiology that stated the expert panel for Regional Anesthesia and Pain Medicine “felt strongly that although the US Food and Drug Administration has not approved chlorhexidine before lumbar puncture, it has a significant advantage over povidone iodine because of its onset, efficacy, and potency” and commented that “interestingly, povidone iodine is also not approved for lumbar puncture.”6 Chlorhexidine (CHG) or tinctures of CHG antiseptic solutions have been used extensively in and outside the United States for regional anesthesia procedures.7
The US Physician Desk Reference (PDR), as of 1984, warns that “chlorhexidine gluconate is for external use only. Keep out of eyes and ears and avoid contact with meninges.” Before 1984, the PDR did not have the “avoid contact with meninges” warning. There are 2 referenced articles for neurotoxicity, both of which are animal studies. One article, published in 1955, was a study with many chemicals and detergent compounds that were injected into the cerebral spinal fluid of monkeys; neurotoxicity was seen with all compounds.8 A second study published in 1984, based on a rat model, involved injecting a CHG solution into the anterior chamber of the eye. This study showed degeneration of adrenergic nerves and suggested that neurotoxic effects on thin myelinated fiber systems in the CNS should be investigated.9 Since the publication of the 1984 PDR warning, a number of articles have appeared describing the use and efficacy of CHG in regional anesthesia and conclude that it is the preferred skin disinfectant.10,11,12 These papers and accumulated clinical experience have been sufficient to persuade the major specialty society (ASRA) and the majority of clinicians to adopt CHG as the preferred skin disinfectant in the setting of regional anesthesia. To view this from the perspective of the FDA, their reluctance to specifically suggest a label change perhaps arises out of a philosophical reluctance, no perceived need from their perspective, and inadequately powered prospective evaluation of CHG in the setting of regional anesthesia (especially epidural and spinal) to reach their threshold for a labeling change.13 From the perspective of a manufacturer of a CHG skin prep, the expense associated with obtaining a label change is prohibitive. Evidence based guidelines, like those in the Hebl article, make a manufacturer initiated labeling change unlikely. The question raised by Dr Urdaneta should perhaps best be posed to the FDA.
Cynthia T Crosby
VP Global Medical Affairs
- Hebl JR. The importance and implications of aseptic techniques during regional anesthesia. Reg Anesth Pain Med 2006;31: 311-23.
ChloraPrep™ labeling (Cardinal Health). Accessed on August 28, 2008.
Hibiclens® labeling (Mölnlycke Health Care). Accessed on August 28, 2008.
- Committee on Drugs. Unapproved uses of approved drugs: The physician, the package insert, and the Food and Drug Administration: subject review. Pediatrics 1996;98:143-145.
- Beck JM, Azari ED. FDA, off-label use, and informed consent: debunking myths and misconceptions. Food and Drug Law Journal 1998;53:71-104.
- Hepner DL. Correspondence. Anesthesiology 2007;106:879-80.
- Adam MN, Dinulescu T, Mathieu P, et al. Comparison of the efficacy of 2 antiseptic solutions in the prevention of infection from peridural catheters. Cah Anesthesiol 1996;44:465-7.
- Hurst EW. Adhesive arachnoiditis and vascular blockage caused by detergents and other chemical irritants: an experimental study. In: Stewart MJ, Cameron GR, Oakley CL, Collins DH, MacDonald A, eds. The journal of pathology and bacteriology. London: Oliver and Boyd Ltd., 1955. Pp. 167-178.
- Henschen A, Olson L. Chlorhexidine-induced dengeneration of adrenergic nerves. Acta Neuropathol 1984;63:18-23.
- Shapiro JM, Bond EL, Garman JK. Use of a chlorhexidine dressing to reduce microbial colonization of epidural catheters. Anesthesiology 1990;73:625-31.
- Kinirons B, Mimoz O, Lafendi L, et al. Chlorhexidine versus povidone iodine in preventing colonization of continuous epidural catheters in children. Anesthesiology 2001;94:239-44.
- Crowley L, Preston R, Wong A, Book L, Kuzeljevic B. What is the best skin disinfectant solution for labour epidural analgesia? A randomized prospective trial comparing ChloraPrep™, DuraPrep™, and Chlorhexidine 0.5% in 70% alcohol. Anesthesia & Analgesia 2008; 106:A-3.
- Stafford RS. Regulating off-label drug use—rethinking the role of the FDA. N Engl J Med 2008 Apr 3; 358 (14); 1427-1429.