The perils of compounding (Proceedings)
Compounding has been defined by the National Association of Boards of Pharmacy (Model State Pharmacy Act) as the preparation, mixing, assembling, packaging, or labeling of a drug or device, as the result of a practitioner's prescription drug order (or initiative) and based on the practitioner /patient/pharmacist relationship (http://www.iacprx.org/index.html, accessed July 2004). The last two descriptors--prescription driven and in the context of a veterinary (client) patient relationship--are vitally important but often unrecognized or ignored descriptors of the definition. Compounding is and always has been a critical component to the provision of individualized drug care to the small animal patient. The Animal Medicinal Drug Use Clarification Act guarantees the right of veterinarians to compound. However, the science and art of compounding are also guaranteed to pharmacists, a profession more properly trained in pharmaceutics (although not necessarily compounding). The sole justification for prescribing or dispensing a compounded preparation relates to the patient: no commercially available preparation is available which will meet the needs of the patient. Cost is NOT a justifiable reason for pursuing a compounded product. Many reasons exist for the veterinarian to use compounded products judiciously. These include legal and ethical reasons, all of which have been addressed in a comprehensive review of compounding for small animals (Vet Clin North Amer, in press; September 2006). Among the reasons are the lack of oversight by any state or (with the most recent federal court rulings) federal government oversite of the compounded product. Accordingly, no assurance can be provided regarding the quality, safety or efficacy of compounded product. Transdermal gels offer an example of both the best and worst considerations regarding the availability of novel drug delivery systems that are compounded.
Historically, drug use began with compounded medicinal agents, leading to the practice of pharmacy. Human compounding has undergone a dramatic swing for a variety of reasons, many economic, but others the need to individual drug therapy for special patient populations, such as geriatric and pediatric patients. Compounding has always been an important source of veterinary drugs. The lack of animal approved drugs, and the need for formulations for exotic or small animals mandated the need for compounding of veterinary drugs. However, compounding by pharmacists has taken a recent and dramatic upward turn. The growth of veterinary compounding has been a healthy adjuvant to the profession. The availability of compounding services enhances the veterinarian's ability to safely and effectively treat patients. Compounding may prove critical for certain species such as cats and exotics. Compounding can fill the need for previously prepared antidotes for use in cases of animal poisonings. Compounding offers convenience. Under appropriate conditions, several drugs might be combined in a single dosage form for administration to a noncompliant patient. Novel drug delivery methods may allow more effective treatment--and safer administration–-to fractious animals. However, the attributes of compounding also are balanced by detractors. Reformulation of any drug product into any compounded form, or the formation of a compounded product from pure drug should cause veterinarians to question the safety and efficacy of the product being dispensed or prescribed. Ethical and legal issues surrounding compounding of veterinary drugs often differs from human products. Unfortunately, often neither animal care givers, veterinarians or pharmacists may be aware of the differences between human and veterinary compounding. It is the veterinarian's responsibility--not the pharmacists'--to assure that compounded medications intended for the treatment or prevention of diseases in animals is both safe and effective. Accordingly, veterinarians must carefully consider the ethical, legal, and safety issues associated with use of compounded veterinary drugs.
In the early 1920's, an unpatented sulfonamide antimicrobial was discovered. Within a short perod of time, many manufacturers were making hundreds of sulfonamide antimicrobials. One of the products was prepared in ethylene glycol (antifreeze). Over 100 people--including children--died. At the time, no regulatory agency evaluated drug products prior to their market. However, this incident lead to the Food and Drug Administration's role in the premarket assessment of drug safety. In 1968, the FDA assumed the role of assessing efficacy as well. Whereas approved animal or human drugs have undergone rigorous, scientific testing to ensure drug safety and efficacy for the patient, compounded products have not. Although pharmacists are directed to compound from written protocols and to maintain written records of compounding activities, currently pharmacists are not required to assure accuracy in product preparation, including product stability. Although a reputable pharmacy may randomly check accuracy of selected drugs, this act currently is voluntary and will be limited to selected drugs and aliquots. Although guidelines exist for establishing expiration dates of compounded products, dates are not necessarily based on scientific data and may not be followed. The risks associated with failed delivery (too much or too little) of a compounded product are added to risks associated with the approved finished dosing form of a drug. The more sophisticated the preparation, the more likely adverse events will occur because of diminished or excessive drug delivery. Few published reports exist that delineate adverse events resulting from inappropriate compounding. Despite indications of frequent problems with compounded products, the FDA receives few reports regarding adverse events related to compounded products. This reflects, in part, the lack of mandated adverse event reporting. However, it also reflects the difficulty in recognizing therapeutic failure due to failed delivery, The latter is likely to be detected only if it is sought and if the drug or response to the drug can be easily monitored. A variety of studies have focused on accuracy in labeling of compounded products, particularly in equine medicine. Products found to be mislabeled include omeprazole, ivermectin (both pirated drugs), ketoprofen (one product contained only 50% of the labeled content, whereas 12 of 13 contained close to 100%), amikacin (percent of labeled content ranged from 59 to 140%; none were within 10%), and boldenone (all within 15% of labeled content, but 2 of 5 contained up to 5% of impurities.Potential Errors
Compounding from bulk substances is easier than from approved finished dosing forms because excipients or other materials do not interfere with product preparations. Further, excipients in the finished dosing form will not interfere with dissolution of the drug in the vehicle. However, the use of an approved finished dosing form of a drug for compounding offers a major advantage to use of a bulk substance in that the approved drug has passed stringent tests of analysis regarding drug purity and potency, and the absence of contaminants. As such, products formed from bulk substances are associated with greater risks compared to products compounded from approved drugs because the approved version has passed stringent tests of analysis regarding drug ingredients and presence of contaminants. In contrast, for bulk substances, the burden of purity and accuracy lies with the pharmacist and there is no mechanism to assure that the burden has been met. All products, active ingredient or excipients (fillers, preservatives, etc), domestic or foreign, should either meet United States Pharmacopeia (USP) or equivalent standards; or should be purchased after FDA inspection. However, bulk substances increasingly are being acquired by compounding pharmacies from non-inspected foreign (particularly Asian) sources at a price much lower than their domestic counterparts. Drugs which are still under US patents are often obtained in this manner. Bulk substances will be accompanied by a credible certificate of analysis. The need for validation of ingredient source (including all active and inactive substances) is paramount as inexpensive bulk substances increasingly are being acquired from non-inspected foreign (particularly Asian) sources. The active drug in a compounded product might also be substituted for an alternative drug; the substituted drug may not be characterized by the same pharmacokinetic or pharmacodynamic characteristics (also, see mathematical errors) and veterinarians should indicate on prescriptions that unapproved substitutions are not allowed for compounded products.