Compounded drugs and clinical practice (Proceedings)

Compounded drug formulation for use in equine clinical practice has at least two clearly ethical appeals, one contentious issue, and one non ethical practice.

1. Drugs that are not available in commercial formulations useful in horses can be compounded for better ease of administration and clinically effective applications. Also, drugs without Food and Drug Administration (FDA) approval, human or otherwise, can be formulated. This is the essential function that pharmacy compounding fulfills, because there is a large need for medications in equine practice relative to the small number of drugs FDA approved for horses.

2. Compounding of drugs that have been approved for horses, but have been withdrawn by the sponsor is fair game for compounding pharmacies (e.g., oral flunixin meglumine powders, or dipyrone injectable). Again this is an essential function fulfilled by compounding pharmacies.

3. Compounded drugs are often far less expensive than FDA approved formulations for other species, especially those approved for human beings. Compounding of these formulations is a contentious issue. By the letter of the guide this is inappropriate compounding. However, expense of products approved for human beings can preclude treatment. It is the author's opinion that if the veterinarian and the owner are aware of issues in using compounded drugs, this is a rational use for them.

4. Compounded drugs that mimic FDA approved drugs are often far less expensive than FDA approved formulations for horses. This is the disturbing form of compounding that has a severe negative impact on drug development and equine practice. In addition, this is an unethical practice as defined by most pharmacy boards and good compounding practice. As an example, using compounded omeprazole, clenbuterol (both for oral use), or flunixin meglumine, (for iv use) in horses is not advisable or appropriate on several levels. Quality of clinical medicine, negative impact on equine drug development, and client expectations are just a few issues. The quality of the compounded medication cannot be guaranteed. Hence, it is reasonable to assume that this increases your liability, and reduces the quality of care delivered. Compounding of these drugs is considered unethical by the AVMA.

Veterinary compounded drug quality is greatly unregulated in most states. Essentially quality is dictated by the ethical and knowledge bounds of your pharmacist. Clearly an essential part of rational therapeutic drug use is the knowledge of the quality, strength (concentration), purity and availability of the molecule in the formulation you intend to administer. In this respect, when a compounded drug is prescribed, veterinarians should have complete knowledge of the compounding pharmacy selected for this process, since the veterinarian bears a portion of the responsibility for the use of these formulations. In addition, veterinarians must decide when quality is outweighed by cost. In other words, when is a clinical decision to use a compounded medication worth the risk of ineffectiveness or adverse responses in the patient and to the client.

It is judicious for veterinary practitioners to assume that they are ultimately responsible for the use of a compounded product. This more clearly defines the seriousness of using compounded formulations. Clearly, it behooves the veterinary practitioner to be sure that the compounding pharmacy is following appropriate compounding pharmacy laws and guides.

Regulation of compounded drugs

Knowledge of a drug's strength and availability to a patient is essential to achieving a positive effect. If practitioners choose to compound, or to prescribe compounded medications prepared by a pharmacist, they may be accepting the responsibility for the formulation's effectiveness, safety and composition. FDA approved drugs are consistently formulated to specification. Assurance of a formulation's composition or its availability to the patient is less certain when veterinarians prescribe compounded medications. Therefore, the veterinarian must collect specific information to aid in the identification and choice of a quality compounding pharmacy. However, remember that even with compounding pharmacies with high quality standards, there is little scientific information for the pharmacologic characteristics of compounded formulations in animals. Some pharmacies have incorporated analytical techniques (e.g., HPLC), but this practice is not widespread.

Federal and state compounding regulations and guidelines do little to monitor quality of product. Compounding of animal drugs is regulated principally by the Food and Drug Association (FDA) at the federal level and pharmacy boards at the state level. FDA regulates compounding through the Federal Food Drug and Cosmetic Act. Federal regulations regarding compounding are located in Section 21 of the Code of Federal Regulations, Part 530 entitled "Extralabel Drug Use in Animals." Also, FDA's policy regarding compounding can be found in the Compliance Policy Guide 608.400 entitled "Compounding of Drugs for Use in Animals." Veterinarians are encouraged to read these documents, as well as the pharmacy board laws and guides in their respective states, to get a more complete understanding of the legal requirements. However, even with federal and state regulatory oversight there can be quality issues associated with compounded products.

State pharmacy boards perform annual or biannual inspections and are effective at responding to complaints. If you believe that a pharmacy is performing in an unethical manner (e.g., compounding for lay-persons, not providing the drug in the prescribed concentration, etc.), then you should to file a report to your state pharmacy board. (www.avma.org "Addressing, prescribing and dispensing in your practice")

Provisions in federal and state laws also apply to veterinarians, if they find themselves in situations where the only choice for treatment is a compounded medication. Use of compounded medications is bound legally and ethically by several stipulations that include, but are not limited to, the development of a veterinarian-client-patient relationship, prescription drug dispensing restrictions, and use in the treatment of disease or to improve welfare of the animal. In addition, there should be no FDA commercially available approved product in a suitable dosage form to treat the condition (e.g. a need for an IV formulation, when only tablets are approved).

Economics

Cost versus the use of FDA approved formulations

Compounding of formulations for routes that are the subject of a New Animal Drug Approval (NADA, FDA veterinary approval, see http://www.fda.gov/cvm/greenbook/) for use in horses or food animal species is not appropriate according to good compounding practice guidelines in almost every state. Since the ethical nature and compounding knowledge of the pharmacist is essential to the quality of compounded drugs, then it could be assumed, but not guaranteed, that pharmacies that provide this service may be suspect in terms of providing quality product. However, the cost of some formulations that are the subject of a New Drug Approval (NDA) for use in persons or small animals may preclude the use of these drugs for veterinary practice. In this case compounding may be rational and clearly arguable.

Cost and choosing a compounding pharmacy

Quality is paramount in the choice of a compounding pharmacy.

Cost and increasing profit

It is inappropriate to compound drugs to increase a practitioner's profit margin when an approved formulation for that species in the desired route is available. As an example, veterinarians distributing pharmacy compounded clenbuterol for oral administration is inappropriate simply because the margin is higher.

Information specific to the compounding pharmacy

Some of the questions presented here are not issues directly related to quality drug compounding, but relate to the conduct of the practice of pharmacy compounding. If a compounding pharmacy does not follow state pharmacy guidelines relative to the practice of pharmacy medicine, can one be sure they are following state pharmacy guidelines in relation to compounding practice for veterinary species? For specific compounding guidelines, contact your state pharmacy board.

Does the compounding pharmacy ship products interstate?

Shipping compounded drugs interstate is appropriate if the drug is prescribed by a veterinarian. However, many state pharmacy boards require that a pharmacy that ships drugs to another state must be registered in the state of destination. Again, a compounding pharmacy that neglects to adhere to this requirement should be suspect. Also, there is a large question as to the liability assumed by the veterinarian assumes if he/she is the recipient of a drug shipped interstate and illegally. Many compounding pharmacies comply with this regulation. It behooves the veterinarian to be sure they have.

Does the firm compound medications for laymen without a prescription?

If the answer is yes, then the compounding pharmacy has gone far beyond the bounds of good compounding practice and pharmacy board guidelines. One should suspect the actions of these compounding pharmacies. The quality of the products from these firms should be suspected. Invariably, this action is not approved by pharmacy boards or guidelines which specifically state that compounding of drugs should only occur by request of medical professionals and by contemporaneous prescription. This activity has been deemed unethical by most state pharmacy boards.

Is a licensed pharmacist on staff?

Compounding may be legally performed only by a licensed pharmacist or veterinarian. Pharmacists have the training, and legal and ethical responsibility to follow good compounding practices as prescribed by the practice of pharmacy, and as outlined by the attending jurisdictions (the state pharmacy boards). Pharmacists must adhere to the national Association of Boards of Pharmacy, Good Compounding Practices or the equivalent state good compounding regulations and guides. Pharmacists have the training to understand the issues of quality, strength, purity, bioavailability, and stability essential to rational use of drugs. Some compounders do not have pharmacists on staff or there is at best a loose association between the compounding firm and a pharmacist. To avoid this situation, veterinarians should identify the pharmacist, and verify the name and state license number.

If bulk product is used to produce the compounded formulation, are these raw materials of high quality?

In most situations, the use of bulk chemicals is needed for compounding drugs for use in horses and other non-food companion animals. Clearly, the raw materials must be of high quality. Good Manufacturing Practice (GMP) ensures that the product contained in an FDA approved formulation has the quality attributes identified by its label and certificate of analysis. Good manufacturing practices provide for the controls necessary to assure that the resultant product has and retains the intended identity, quality, strength, and purity. Quality compounding pharmacies can usually provide certificates of analyses (COAs) for the bulk drug they use with your ordered formulation. COAs alone do not assure the quality of their bulk raw material. Drug manufactures verify the COAs on an annual basis. Some compounding pharmacies do not verify the quality of their raw materials, and simply find the least expensive source regardless of the manufacturing controls. At a minimum, one should ask the compounder if the wholesaler of the bulk drug is licensed, or registered, with the state pharmacy board. In addition, and minimally, the bulk product should be a United State Pharmacopeia/National Formulary (USP/NF) listed product.

It is important to note that using raw materials to compound drugs intended for use in food animals or for use in horses intended for human consumption is subject to regulatory action with the rare exception of those medicaments that are permitted to be compounded by the FDA Center for Veterinary Medicine. This relates directly to the lack of assessment of the safety of these products in terms of food residues. Where horses are companion animals, and not used. For food, the use of bulk products for compounding would not ordinarily be considered for regulatory action where animal health is not threatened, and there is not a significant risk of diversion of the bulk drug or compounded drugs for use in food animals.

What type of quality testing is performed?

Batches of the final compounded product should be quality tested for strength, potency and content. Unfortunately, this is impractical in many situations. Nevertheless, if a compounded formulation is produced on a regular basis for a large group of animals some form of test batch analysis should be expected. Even when USP/NF bulk drug of know strength and quality are used, loss of active ingredient or formulation errors may occur during compounding. Analysis of the compounded drug should be performed after the compounding process is complete. Quality compounding pharmacies will test commonly prescribed recipes for their own quality control in terms of potency, strength, shelf life, etc. I recommend that if a compounded drug is used on a regular basis, the veterinarian collect a sample to be sent for analysis to a certified laboratory. Some state racing laboratories can assist you in this.

The expiration date. Are stability data available?

The nature of equine practice stresses the stability of drug products. We tend to work outdoors (not a temperature controlled environment). Chemists cannot predict, with great confidence, the stability of formulated products without data from controlled stability studies. Regardless of the testing available, the expiration date should be set at the time a prescription is entirely used. The compounding pharmacy should give some advice on storage of the formulation. Compounding pharmacies giving expirations in periods of months or years often do not actually have the data to provide this information.

Other considerations

Equine veterinarians must not take the prescription of compounded drugs lightly. Approved drugs give us the highest assurance of quality, strength, purity and stability, as well as the best opportunity for accurate dosing. Dramatic changes in drug disposition (i.e. bioavailability) often occur with minor changes in compounding technique, even while using the same recipe.2 In addition, approved formulations undergo rigorous tests under various environments to define the limits of storage conditions. This assures us that under conditions of use the approved drugs are reasonably stable.

Veterinarians rarely have the ability to establish drug stability, physical and chemical compatibility, and pharmacodynamic action of the drugs they use. Ethically, we must take responsibility for the use of compounded drugs. To do so, we must collect information on the practices of individual compounding pharmacies. In addition, we must depend on licensed pharmacists to provide us with well compounded drug formulations. It behooves us, our clients and our patients to become informed of the quality of product produced by firms we choose to compound our needed formulations.

References

Upson D. AVMA guidelines on compounding. J Am Vet Med Assoc 1994; 205: 199-200.

Riviere JE. Influence of compounding on bioavailability. J Am Vet Med Assoc 1994; 205: 226-231.

The Animal Medicinal Drug Use Clarification Act of 1994 (AMDUCA) allows permits and regulates extralabel pharmacy compounding. It has specific labeling requirements, recordkeeping requirements, advertising and promotion prohibitions, and layman-use prohibitions. (www.fda.gov/cvm/index/amducca/amducatoc.htm)

Drug compounding is legal if: no approved drug for animals or humans exists, the compounding is performed by licensed pharmacist or veterinarian within the scope of professional practice, adequate procedures and processes are followed to ensure safety and effectiveness, all relevant States laws relating to compounding of products are adhered to and the scale of compounding is in line with the established need for compounded products. Extralabel use must be by or on the order of a veterinarian within the context of a valid veterinarian-client-patient relationship.

Why is CVM making illegal compounding a priority? The manufacturing controls, experience and skills of the producers, and the research and testing needed to assure the quality of the drug products is missing. The quality of the ingredients and manufacturing process is unknown. The Center for Veterinary Medicine (CVM) believes that most "compounding pharmacies" in business today start with bulk drugs, in clear violation of AMDUCA provisions. However, although nothing in AMDUCA or its regulations permits drug compounding from bulk drugs, the CVM Compliance Policy Guide 608.400 entitled "Compounding of Drugs for Use in Animals" does allow for use of bulk chemicals as long as the compounded product is not intended for use in food animals.

Internet pharmacies advertise medications on television, internet websites, by direct mail catalogs, through promotions and appearances at various trade shows and professional conferences. They may try to contact client's veterinarian, or use one of their own "staff" to write the prescription. No veterinarian-client-patient relationship Internet pharmacies prescriptions have resulted in wrong medications or strengths.