Compounding issues: quality, safety, and efficacy (Proceedings)

Individualized drug therapy increasingly is being recognized as an important aspect of health care for both human and veterinary medicine. Consequently, veterinarians must reach beyond FDA-approved veterinary products to provide the current standard of veterinary care to their patients. The lack of commercially - available drug formulations often leads the veterinarian to prescribe or dispense a product specifically designed and compounded for their patients' medical needs. 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.

Clearly, compounding is and always has been a critical component to the provision of individualized drug care to the small animal patient. However, 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. 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. Use of a compounded product may put the practitioner in a situation where civil liability (rather than criminal liability) is a concern. Transdermal gels offer an example of both the best and worst considerations regarding the availability of novel drug delivery systems that are compounded. Just because a product can be made does not mean it will work (or that it is safe); standard of care criteria upon which liability issues are based are likely to no support decisions that support compounding if an alternative approach is available.

Among the important aspects to recognized regarding compounding is their difference from generic products. Generic products are approved products that contain the same ingredients, in the same form as the pioneer product (or another already approved generic product). As such, generic products undergo full FDA approval. However, although not related to compounding, it also is important to recognized that while generic drug preparations in general behave the same as the pioneer drug, this is true only for the target species. In otherwords, if two generic forms of a human drug (eg, zonisamide) exist (A vs B), both A and B can be expected to behave the same as zonisamide in the person. However, neither A nor B should be expected to behave the same in the dog (if it is a human generic drug) nor should A be expected to behave the same as B in the dog. If, however, it is a canine generic, then the expectation would be that the drug would behave the same in the dog.

It is important to recognize the Congress has not given the FDA the power to regulate compounding, or even the compounded products. The act of compounding is regulated at the state level; however, Boards of pharmacy are quite variable in their regulations, sometimes in conflict with the federal laws. The FDA regulates fixed dosing forms which might be used to compound a preparation but does not regulate the end product, nor does it regulate bulk substances which might be used to compounde a product. The majority of bulk substances come from Asia. Already, contamination of bulk substances has been internationally recognized (contamination with cyanuric acid of the contaminate melamine for pet food products; contamination of heparin with hypersulfated glycosamine glycans). Although a reputable compounding pharmacy will assure a paper trail exists for products that they use, even certificates of analysis can be falsified or modified. The availability of bulk substances facilitates the manufacturing (rather than compounding) of compounded products that several nationally recognized pharmacies implement. Pharmacies that do such manufacturing place labels on the products that easily are mistaken for approved labels (e.g, KBroVet®). Among the difficulties of the FDA in controlling such manufacturing is, again, limitations set by congress not only in activity but in fines. Further, pharmacies that are found to be in violation of state (rather than Federal) laws simply move to another state.

Quality assurance of the product should be of concern. 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.

Ingredient 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. 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.

Mathematical errors

Mathematical errors are probably the most common reason for pharmaceutical compounding errors, and potentially the most lethal. Compounding is predisposed to mathematical mistakes because, by its nature (prescription driven, small volumes), much of the equipment and technology that facilitates accuracy and precision of finished dosing forms is not (should not be) used. In addition to the source of the ingredient, pharmacists may substitute drugs without acquiring clinician permission. Mathematical errors may also reflect substitution of the active ingredient. For example, the content of active drug content may differ as is demonstrated by metronidazole. The recipe for metronidazole benzoate should contain 1.6 mg for each 1 mg metronidazole hydrochloride (or the dose must be similarly increased). Bromide offers another example: 1 gm of the sodium bromide contains more bromide (774 mg) than the potassium salt (692 mg).

Preparation and Storage Errors

Chemical reactions (oxidation, reduction, hydrolysis) are facilitated by changes in humidity, light, pH, presence of oxidizing trace metals, and increasing environmental temperature. 12,13 Excipients may enhance instability due to changes in pH or the presence of disintegrating agents. Degradation products (drugs or excipients) can cause adverse events. Excipients which are critical to the finished dosing form increase the risk of instability in product compounded from an approved source. Whereas approved products undergo intensive scrutiny in regards to stability and potency, compounded products do not; recipies for compounded preparations rarely are associated with studies that assure stability or delineate conditions for storage.

Simple syrups (which tend to be acidic), preservatives, combination drugs, or other ingredients can alter drug pH, and thus, ionization (diffusibility) or stability. The more drugs mixed together in a single preparation, the greater the risk of chemical drug interactions. For example, weak acids and weak basis are likely to chemically inactivate one another. Interactions may occur between the drugs or excipients. For example, only 54% of a fluorinated quinolone (orbifloxacin) was found to be present when prepared in Lixotinic® as a vehicle compared to simpler syrups.

Particle size

Compounding from approved drugs (legal) is more difficult than from bulk drugs (illegal) because excipients are more likely to result in undissolved macroscopic or microscopic precipitates which indicate undissolved and thus nondiffusible, ineffective drug. Sedimentation of undissolved particles may result in caking at the bottom of the drug receptacle; difficulty in shaking or rapid sedimentation (common) after shaking can result in erratic and unpredictable doses. Crushing of any oral tablet may result in unequal particle sizes in the preparation, which in turn will yield different surface areas and different rates of absorption. Fine crushing of the product such that it is no longer a suspension increases the concentration of soluble excipient ; chemicals, including those added to the finished dosing form to facilitate degradation, can cause drug instability. Crushing an oral tablet for preparation in a syrup may also lead to unequal distribution of dissolved drug in the finished preparation and mixing the drug such that it is equally distributed throughout the preparation may not be possible. Repackaging oral tablets or capsules into smaller dosing units may also impact drug efficacy. Diluents such as starch and dextrose might impede oral absorption. Preparation of an oral formulation from an injectable solution in order to enhance accuracy of dosing is more likely to be inappropriate if the drug salt is different between the preparations. If the injectable product is presented in powder form, the drug is likely to be unstable in liquids and may be destroyed when added to liquid (oral solutions). The addition of flavoring agents to oral products may increase drug instability due to changes in pH or the increased risk of microbial growth (ie, with syrups).

Selected commercial oral preparations have been formulated to alter (slow or facilitate) drug delivery and reformulation of such products should be avoided. Compounding altered release products from bulk substances requires sophisticated techniques not generally available through pharmacists. Enteric coated or spansule products should not be crushed. Although spansule products might be reformulated without crushing, the amount of drug in each spansule is not necessarily predicatable and random distribution of drug content is likely to yield erratic dosing. Cyclosporine is a complex molecule characterized by poor oral bioavailability; oral absorption requires bile acids or special formulation as a microemulsion product. As such, it is an example of a drug for which compounding should be approached cautiously, and be supported by therapeutic drug monitoring. In the author's drug monitoring laboratory, cyclosporine blood concentrations were not detectable (two different samples, two weeks apart) in one cat receiving a product compounded from an approved microemulsion human product. Following recommendations that the untampered animal approved version be used at the same dose, concentrations expected at the administered dose were detected within one week of the change in drug product.

Injectable products

Administration of injectable products is inherently associated with a higher level of risk compared to administration of topical or oral products because of more rapid drug delivery, the risks associated with administration of suspensions rather than solutions, the potential impact of impurities (including endotoxin), and the need for sterility. Actions taken to assure sterility and removal of impurities may cause drug degradation. Endotoxin (which is essentially ubiquitous in the environment) is difficult to a remove. Without testing, its absence is impossible to document, yet, its presence can be lethal. The USP has generated guidelines and state laws generally delineate regulations specifically for the compounding of injectable products. Veterinarians should be reluctant to prescribe compounded injections and when doing so, must be confident that the compounding pharmacist follows these critieria.

Topical products

Although administration of topical products generally is associated with fewer risks compared to systemic products (the exception would be ophthalmic products, which also should be sterile), compounding the proper product can be challenging. The USP has promulgated guidelines for the compounding of topical ingredients, including guidelines are designed to assure drug dissolution and drug movement from the vehicle into the skin. For example, solid ingredients should be reduced to the smallest reasonable particles size and the active ingredient should then be added to other substances necessary to dissolve the drug in order to achieve a uniform liquid or solid dispersion. Uniformity of dispersion should be demonstrated by spreading a thin film of the finished formulation on a flat transparent surface. Visual examination of a compounded product should be implemented to identify obvious problems with dissolution, etc. Care must be taken to assure ingredients are not caustic, irritating, or allergenic Vehicle selection can be impressively difficult: undissolved drug cannot pass into the skin; drug that has too great an affinity for the vehicle will remain in the vehicle. Transdermal gels offer an example where care must be taken with treatment of compounded preparations.

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.

Adverse events

Currently there is no obvious mechanism for capturing adverse events associated with compounded products. The FDA-CVM Adverse Event Reporting site should serve as mechanism for reporting. The recent loss of horses to clenbuterol overdose or seleneium overdose exemplifies the risks associated with compounded products. However, these came to national attention due to the number of horses involved. Of concern might be the number of ADE that are missed because they are not recognized. Among the difficulties in recognizing and ADE with compounded products is discriminating therapeutic failure due to the compounded product and therapeutic failure because of failed response of the disease. For this reason it becomes important to anticipate the possibility of therapeutic failure. Further, for this reason, it is prudent to avoid the prescribing of novel methods of drug delivery without scientific evidence of either efficacy or safety. These include transdermal gels, slow release preparations, combinations of products.

Conclusion

The advent and growth of veterinary compounding and the increasing role of the pharmacist in drug dispensing, including compounding, should be embraced by the veterinary profession. For selected patients, extemporaneous compounding of prescriptions is both necessary and beneficial for optimal treatment of veterinary patients. However, by its nature, compounding is individualized and fraught with risks of failure. Pet owners should be informed of the risks associated with using a compounded product and consent to therapy based on disclosure that the use of the product may be scientifically unproven. The AVMA's Council on Biologic and Therapeutic Agents has generated a position statement regarding the use of compounded products which offers sage advice. The position statement reminds veterinarians that, although compounded products may have an important role in the treatment of veterinary patients, compounding may alter the ability of the product to delivery drug and compounding should be reserved for those instances in which there is a legitimate need, and, unless there is no alternative, for which evidence of efficacy or safety exists when administered as the compounded preparation. As the pharmacy profession increases its efforts to define and assure its role in veterinary medicine, and as the regulatory agencies consider changes in the regulations which increase the flexibility of animal drug compounding, the veterinary profession must "step up to the plate", and implement actions that will protect the patient and the public. This has begun with the formation of a Pharmacy Compounding Accreditation Board (PCAB; www.pcab.info) which has promulgated a robust program of accreditation. Volunteer in nature, a pharmacy that has become PCAB accredited has proven that it follows those actions recommended by pharmacists that will minimize the risks to patients or practitioners. Currently, only a small number of pharmacies are PCAB accredited (see website), with nationally recognized pharmacies not yet seeing the need for accreditation. Yet, it is through our prescribing through these pharmacies that our profession can encourage all compounding pharmacists to demonstrate the commitment to our patients that we demonstrate. Finally, although it is the responsibility of the pharmacist to assure the integrity of any finished drug product dispensed to a patient, as the pharmacists will point out when challenged for promoting a product whose scientific support is lacking, it indeed is the responsibility of the veterinarian to assure the safety and therapy of any prescribed therapeutic intervention, and failure to do otherwise places the patient and pet owner, as well as the veterinarian, at risk.

Internet pharmacies

One of the advantages of working with recognized distributors is a decreased risk of clients recieving adulterated or unapproved products. Some internet pharmacies continue to buy "ethical products" from veterinarians (being excluded from purchase by the manufacturer) and then resell these to clients. However, some of these products also have been obtained from other countries. As such, these products are not approved for use in the US, even though the ingredient and packaging is the same. Most problematic is the risk of counterfeit products. This has not become a large issue yet in veterinary medicine, but in human medicine, counterfeiting has become so lucrative that some countries have shifted from cocaine production to counterfeiting. Products tend to be the most popular (e.g, Viagra). The counterfeit product mimics the real in terms of tablet presentation and packaging.

This manuscript represents a portion of the paper Boothe DM: Veterinary Compounding in SmallAnimals: A Clinical Pharmacologist's Perspective published in Veterinary Clinics of North America, September 2006; and Drug-Induced Disease, Small Animal Clinical Pharmacology and Therapeutics, Boothe DM.