March 01, 2013

 

 Unraveling the confounding world of compounding

By Michael J. White
Posted Feb. 13, 2013​  

Dr. Jeff Gerlesits examines a hyperthyroid cat on a busy afternoon, assisted by veterinary technician Merre Bacot.
(Courtesy of Kira Mayne)
 
Evenings can be extremely busy at University Hills Animal Hospital, located on the southern edge of Denver, and this Thursday is no different. Dr. Jeff Gerlesits shakes his head as he finishes an appointment with the kind of patient many veterinarians fear: the 15-year-old, hyperthyroid cat whom the owner swears “is stubborn as a mule, fast as lightning, and simply will not swallow any pills.”
 
“It’s amazing how many of these animals seem to share the gift of speed, yet sleep 18 hours a day and move only to stretch or grab a bite to eat,” Dr. Gerlesits laments, jokingly. Still, the problem is clear: What began as a relatively straightforward diagnosis and plan of care has now become much more complicated.
 
At such times, many veterinarians turn to compounding as an alternative means to deliver required medications. Compounded medications offer benefits to veterinarians in certain circumstances, but must be used judiciously.
To provide the highest level of care, prescribing veterinarians must be aware of the benefits and consequences of using these formulations, and must communicate this information effectively to clients. In addition, veterinarians should be familiar with liability concerns associated with the use of compounds to safeguard against legal ramifications. 

Reaching for compounds

The AVMA defines compounding as “the manipulation of a drug, other than in accordance with the FDA-approved label, to make a different formulation of the drug to meet the needs of a specific patient.” Use of compounded medications offers myriad benefits to veterinarians, particularly when dealing with animals that require very small or very large doses of a particular medication or with patients such as Dr. Gerlesits’ hyperthyroid cat, for which the traditional route of administration might not be optimal or even feasible.
 
The ongoing, rapid growth of the compounding industry is a testament to the importance of compounding in human and veterinary medicine. Yet, the benefits of compounded medications are not as cut-and-dried as some would like to believe, and the recent human outbreak of fungal meningitis linked to the New England Compounding Center underscores the potential dangers associated with inappropriate compounding practices. Notably, compounded medications are not approved by the Food and Drug Administration and are not subjected to the stringent testing required for traditional medications. Thus, compounded medications, even those derived from the purest ingredients and prepared under the most stringent conditions, offer no guarantees of efficacy, bioavailability, stability, or safety.
 
Despite these inherent issues, compounding is an essential tool that provides therapeutic flexibility for difficult or irregular cases. But, compounded medications should be used judiciously, and veterinarians should ask themselves a series of questions before using compounded medications in their treatment plans.
 
What is compounding?
Compounding is the manipulation of a drug, other than in accordance with the FDA-approved label, to make a different formulation of the drug to meet the needs of a specific patient. In this context, “manipulation” includes mixing, diluting, concentrating, flavoring, and changing a drug’s dosage form.
 
Examples of compounding are crushing tablets to make an oral suspension or topical cream (for example, using methimazole tablets to make a transdermal gel for treatment of a hyperthyroid cat), adding flavoring to a commercially available drug to make it more palatable, and mixing two injectable drugs in a single syringe. 
 
 
"Compounding may impact the absorption and depletion of a drug. This may result in drug concentrations that are above or below the therapeutic range.”

Dr. Butch KuKanich, chair, AVMA Council on Biologic and Therapeutic Agents Issues 

 
 
Are compounded drugs the same as generic drugs?

Compounded formulations are not the same as generic, or “nonproprietary,” drugs. While typically less expensive than their brand-name counterparts, generic drugs are regulated by the FDA and undergo an abbreviated new animal drug approval process. For this reason, they are guaranteed to be bioequivalent to the brand-name product (within a 90 percent confidence interval) and have been determined to be safe and effective.
 
Moreover, manufacturing facilities that produce generic drugs are subject to FDA inspection. The agency routinely analyzes the finished product to ensure it contains the correct amount of drug and is free of contaminants, and performs dissolution tests to ensure the product consistently and predictably dissolves in the gastrointestinal tract following oral administration.
 
In contrast, the FDA does not approve compounded medications or inspect the facilities where they are produced, so bioequivalence, efficacy, and safety cannot be guaranteed.
 
When is it legal and acceptable to use a compounded formulation?
According to the “Compounding” policy developed by the AVMA Council on Biologic and Therapeutic Agents and accepted by the AVMA Executive Board, the decision to use a compounded drug should be veterinarian-driven and governed by the veterinarian-client-patient relationship.
 
The COBTA chair, Dr. Butch KuKanich of Kansas State University, explains, “The FDA’s extralabel drug use rules allow compounding of FDA-approved medications under certain conditions. Namely, compounding should be limited to drugs for which both safety and efficacy have been demonstrated in the target species, disease conditions for which response to the therapy can be monitored, and for those patients for which no other method or route of delivery exists.”
 
Laws that govern compounding vary from state to state, so the AVMA advises that state rules be reviewed and followed. For example, some states allow veterinarians to prescribe and administer compounds to patients while they are at the practice, but it’s not legal for a veterinarian to dispense previously prepared compounds from a pharmacy to clients, aside from a narrow exception in California.  
 
When is it illegal or unethical?
Compounding is intended to meet the needs of specific patients. Thus, it is illegal to compound large quantities of drug not intended for use in specific patients, particularly for the purpose of reselling the compounded medications to practitioners or owners.
 
Additionally, the FDA’s extralabel drug use rules and Compliance Policy Guide strictly prohibit the compounding of medications for use in animals from bulk, or “raw active,” ingredients. Introduced in July 2003, the CPG prohibits the use of bulk ingredients to help control the use of compounded medications in food-producing animals and to safeguard against the mass production and wholesale manufacturing of compounded products.
 
The AVMA contends that, in some instances, it is necessary to compound certain drugs for use in nonfood animals from bulk substances, such as times when the approved drug is not commercially available or the needed compounded preparation cannot be made from the approved drug, e.g., in the compounding of certain sterile ophthalmic preparations.
 
Nevertheless, until changes are made at the federal level, the FDA’s policy remains that compounding from bulk pharmaceutical ingredients for veterinary use is illegal, save for compounding of a small group of poison antidotes listed in the CPG. 
 
How can a veterinarian ensure that a compounded formulation is bioavailable?
A veterinarian can guarantee that a compounded medication is bioavailable only by monitoring blood concentrations of the active ingredient, “a very viable and affordable option,” according to Gigi Davidson, a registered pharmacist and director of clinical pharmacy services at North Carolina State University. As an example, she says, “Patients receiving compounded cyclosporine should absolutely have their blood levels checked to see if they are reaching the therapeutic range, which in most cases they are not.”
 
In instances when blood concentration monitoring is not feasible, practitioners should consult published scientific studies that illustrate the efficacy and stability of a particular preparation in the target species and should ask their compounding pharmacist to do the same.  
 
Still, Dr. KuKanich warns, “Veterinarians can rarely ensure that a medication is even stable in the compounded formulation. We need to be aware that compounding may impact the absorption and depletion of a drug. This may result in drug concentrations that are above or below the therapeutic range and lead to the development of an adverse drug event, including therapeutic failure.”
 
For this reason, therapeutic monitoring­—including close communication between the veterinarian, owner, and pharmacist—is essential when designing a treatment plan that includes compounded medications.
 
 “It’s not the ideal situation,” Dr. Gerlesits explains, “but as a veterinarian,
you quickly learn to improvise."
 

Dr. Jeff Gerlesits, University Hills Animal Hospital, Denver










If an animal develops an adverse event associated with a compounded drug, who is held accountable?
The issue of liability associated with the use of compounded medications is difficult to pin down, according to the AVMA PLIT. Dr. Linda Ellis explains, “It is difficult for PLIT to give any blanket statement, because we don’t know the facts of a claim until it is received.”  
 
Some factors that must be considered are the motivation behind using a compounded product, the inherent risks associated with the particular medication, and potential errors that could occur during the compounding process.
 
“There may not necessarily be negligence simply because the animal suffers an adverse event,” Dr. Ellis continues. “But if there are signs of an adverse reaction and the veterinarian does not recognize them, then that may be considered below the standard of care.”
 
Davidson said, “While the pharmacist may be liable for any quality-related problems with compounds, the veterinarian is accountable for what happens to the patient.” She cautions that practitioners should understand that, even if evidence exists regarding the safety of a formulation, they are responsible for ensuring that the medication achieves the desired effect.
 
Are pharmacists trained to compound for animals? If not, is there a way to choose a pharmacist who will best formulate the desired compound?
In general, veterinary pharmacotherapy is not included in pharmacy school curricula. Davidson explains, “The only credentialed veterinary pharmacy specialists are those pharmacists that have achieved diplomate status in the International College of Veterinary Pharmacists.”
 
Currently, there are only 19 credentialed veterinary pharmacists in the world. “Veterinarians can recognize this status by the diplomate notation of DICVP on pharmacist credentials,” Davidson said. Three veterinary clinical pharmacy residency training programs are offered in the U.S.—at the University of California-Davis School of Veterinary Medicine and at the University of Illinois and North Carolina State University colleges of veterinary medicine.
 
Most training in animal-specific compounding is pharmacist-driven and acquired via continuing education. Given the differing pharmacodynamics of certain drugs in humans versus animals, prescribing veterinarians should seek out pharmacists with additional training and experience in veterinary compounding.
 
In general, the AVMA suggests that veterinarians contact their state board of pharmacy to ascertain the status of a pharmacy’s license and to gain valuable information, including the pharmacy permit number. Veterinarians can also consider whether a pharmacy is certified by an independent body. One such independent body is the Pharmacy Compounding Accreditation Board. A voluntary accreditation program, the PCAB was established in 2004 for the purpose of improving the quality of compounding operations and preparations.
 
The AVMA does not endorse the PCAB or other pharmacy accrediting bodies. Still, Davidson considers the PCAB a potential resource. She said, “All 50 states regulate compounding pharmacies differently and hold them all to different standards. If a pharmacy meets the incredibly rigorous accreditation standards of PCAB, then a veterinarian can be assured that the pharmacy is legally compliant and that its compounds are of the highest possible quality. In at least one state, New Jersey, legislation has been introduced to require all pharmacies compounding sterile preparations to become PCAB-accredited.”
 
If a PCAB-accredited pharmacy is not available, Davidson suggests that the veterinarian ensure the compounding pharmacy is at least compliant with current United States Pharmacopeia standards. She said, “USP standards for compounding offer formulas and practices and default beyond-use dates that should be applied to finished compounds. Compounders extending beyond-use dates past USP default times are creating a higher risk for adverse events due to contamination or compound degradation.”

Advocating for prescribing veterinarians

Considering the confusion surrounding the use of compounded medications, many more questions may arise. Particularly in the area of food animal medicine, the legal and ethical use of compounded medications quickly becomes complicated.
 
Compounding figures prominently on the list of priority issues for the AVMA and the FDA for the 113th Congress, which convened in January. The AVMA Scientific Activities Division is working diligently in conjunction with the AVMA Governmental Relations Division and volunteer leaders such as Dr. KuKanich to address regulatory inconsistencies in favor of prescribing veterinarians.
 
Until a new consensus is reached, veterinarians such as Dr. Gerlesits will continue to use compounded medications judiciously while honoring the VCPR. As for his hyperthyroid patient, transdermal application of methimazole, together with compliant owners and regular monitoring of serum methimazole concentrations, fit the bill, even though this method is not guaranteed to provide therapeutic doses to cats.
 
“It’s not the ideal situation,” Dr. Gerlesits explains, “but as a veterinarian, you quickly learn to improvise. Ultimately, we just need to use the resources available as responsibly as possible.”
 

 
Michael J. White is a second-year veterinary student at Kansas State University and a recent JAVMA News extern.
 
 
 
For the AVMA policies on compounding and other AVMA and FDA resources, visit
www.avma.org and under Knowledge Base click on “Resources,” “Reference Guides,” and “Compounding.”