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Compounding in clinical avian practice.

Compounding is a necessity in clinical avian practice. Although there are benefits to this practice, compounding is also associated with a variety of concerns related to drug safety, efficacy, potency, and bioavailability. There are also a myriad of legal issues that must be considered on both the federal and state level. Obviously compounding is not something that should be entered into lightly. How does your approach to this clinical challenge compare with that of your colleagues? I have invited 7 individuals to share their thoughts and experiences. These individuals are from academia as well as different forms of private practice, from general practice to specialty hospitals. We are appreciative of all the participants for sharing their time and expertise in this Round Table discussion.

Participants include:

* Lisa Carr, DVM, is an associate veterinarian at Maryland Avian & Exotics Veterinary Care, a hybrid general and referral practice in Rockville, MD, USA.

* Hilary Frank, DVM, Dipl ABVP (Avian Practice), practices at North Central Animal Hospital, a small animal-exotics veterinary hospital, which includes an avian specialty service, in Phoenix, AZ, USA. Hilary is also the author of a comprehensive Journal of Exotic Pet Medicine review "Compounding in the Exotic Practice"

* Elizabeth Mackey, DVM, is the co-owner of Sycamore Veterinary Services, a general small animal practice with a large exotics caseload in Athens, GA, USA.

* Olivia Petritz, DVM, Dipl ACZM, is an associate veterinarian at ACCESS Specialty Animal Hospitals in Culver City, CA, USA. Dr. Petritz is also the lead author of a study evaluating the stability of compounded enrofloxacin published in the Journal of the American Veterinary Medical Association.

* Mark Papich, DVM, MS, Dipl ACVP, is a Professor of Clinical Pharmacology, College of Veterinary Medicine, North Carolina State University, NC, USA. Dr. Papich has written and presented extensively on compounding in veterinary medicine.

* Erika Rost, PharmD, is a clinical veterinary pharmacology resident, College of Veterinary Medicine, North Carolina State University, NC, USA.

* Fiorina Tseng, DVM, is Director of the Wildlife Clinic Cummings School of Veterinary Medicine, Tufts University, North Grafton, MA, USA.

I hope that in reading their comments, you will think about your own practice and gain some insight into the decision making process involved in veterinary compounding for clinical avian medicine.

Question: What drives your need for compounded medications?

Dr Tseng:

Because we work with a wide variety of amphibian, reptile, avian, and mammal species, we often find that commercially available drug formulations are not suitable for our needs. Problems include drugs in different concentrations than desired, those that are in a tablet/capsule form, which can be inconvenient for administration to wildlife species, and drugs that aren't palatable enough for oral consumption. We try to be as hands off as possible with our wildlife patients so being able to administer oral medications that will be eaten is key for providing optimal patient care.

Dr Frank:

There are some medications that are not available in a manageable dosage form or concentration that can be easily used for small patients or those that are difficult to medicate.

Question: What is your source for compounded drugs? Local? Internet? Other?

Dr Mackey:

We use several different on-line pharmacies: Roadrunner (Phoenix, AZ, USA), Wedgewood Pharmacy (Swedesboro, NJ, USA), Meds for Vets (Sandy, UT, USA), as well as several local pharmacies. Decision between these is based on cost and how quickly we can get the medication.

Dr Tseng:

We use online pharmacies such as Diamondback Drugs (Scottsdale, AZ, USA), Stokes Pharmacy (Mt Laurel, NJ, USA), or Wedgewood Pharmacy. Occasionally, in an emergency situation, we might use a local pharmacy.

Dr Carr:

Local and online.

Dr Frank:

Unless there is an acute need for a drug within less than 3 days, a local compounding pharmacy is used. In the past, I probably did a bit more compounding in-house. Then a few years ago, the Arizona pharmacy board decided that the way statutes were written, veterinarians were not legally allowed to compound in-hospital for any reason. It took over a year of wrangling to get statutes rewritten, and during that time I realized I had so many options of readily available drugs that when the regulations were changed, I compounded less often. So many medications are used with absolutely no information on effective dose or metabolic pathways for various species. I suspect many patients get better in spite of what we give them!

Dr Petritz:

I predominantly use a local compounding pharmacy, as I know and trust the pharmacist. It is easy to speak with him directly (via phone or in person) if I have any questions or concerns regarding a compounded medication.

Question: What types of compounded drugs do you commonly administer in a compounded format? (Six roundtable participants were asked this question; their responses are summarized in Table I.)

Question: In addition to oral administration, what routes are used for compounded medications in your practice? Nebulization? Injectable? Ophthalmic? Transdermal? Pellet or semisolid pellet? Other?

Dr Petritz:

We primarily use oral compounded medications. Dr Mackey:

Mainly just the oral.

Ms Rost:

Mostly it's different forms of oral like suspensions. One of the previous residents created a gummy worm dosage form for a pet chicken!

Dr Frank:

Nebulization (terbinafine tablets), injectable (leuprolide acetate).

Dr Tseng:

Injectable (buprenorphine compounded to 0.5 mg/mL since we use this drug frequently at a high dose for avian patients).

Dr Carr:

Nebulization, injectable, ophthalmic (occasionally).

Question: Have you purchased single-dose compounded leuprolide acetate from a compounding pharmacy? Would you recommend this practice to your colleagues?

Dr Tseng:

No, I have not purchased this product.

Dr Petritz:

No, I do not use this medication in my practice. Dr Frank:

Twice, many years ago. We do not do this unless there are no other local options such as referral.

Dr Mackey:

We have in the past and never had any problems. I think nowadays we are all more aware of potential complications with compounded medications, and 1 think the risk is greater with an injectable.

Dr Carr:

I have. It's more expensive for the client but a little easier for us. I've had concerns about the patient receiving the correct dose with inevitable loss during reconstitution. The pharmacy that we were using recently was inspected and is no longer offering leuprolide.

Question: Does your practice do compounding in house?

Dr Petritz:

In-house compounding is uncommon in my current hospital for all services, including our exotics service. Mixing the liquid Clavamox (amoxicillin and clavulanate potassium) (Zoetis, Florham Park, NJ, USA) to double-strength (125 mg/mL, by adding half the recommended volume of water) is the most common form of in-hospital compounding we perform.

Dr Frank:

Yes.

Dr Mackey:

Yes.

Dr Carr:

Yes.

Dr Tseng:

Yes.

Question: If yes, what flavoring tricks have been most successful in your patients? Have you had success with specific flavors in certain species or taxonomic groups?

Dr Tseng:

We suspend crushed tablets in Ora-Plus (Perrigo, Allegan, MI, USA) and then dilute with different amounts of distilled water and a cherry syrup for most of our compounded drugs. The cherry syrup works well for most species, carnivores as well as herbivores. Our raptor patients readily consume compounded meloxicam in the cherry syrup suspension in their mice! We do have meat-flavored additives to be used if needed but really haven't found that to be necessary in most cases.

Dr Petritz:

In a recently published study on the stability of compounded enrofloxacin, my co-authors and I examined 3 different flavoring vehicles: cherry syrup and distilled water (50:30 ratio; Humeo Holding Group, Texarkana, TX, USA), corn syrup-distilled water solution (1:1 ratio, Karo dark corn syrup [ACH Food Companies, Oakbrook Terrace, IL, USA]), and liquid sweetener (1:1 with the injectable formulation, Ora-Sweet [Paddock Labs, Minneapolis, MN, USA). Subjectively, the cherry syrup was the best to mask the taste of the enrofloxacin. (1)

Dr Frank:

We use the feline compounding solution (FLAVORx Veterinary System, Columbia, MD, USA) as a carrier, or lactulose in some cases, and a variety of the LorAnn food flavors (LorAnn Oils, Lansing, MI, USA). Strong or bad tasting medication such as enrofloxacin is best masked with citrus flavors. Choosing flavors that are similar to preferred foods for each individual patient can be helpful.

Dr Mackey:

In general, sweeter, fruit flavors work best.

Dr Carr:

We have been using hard candy flavoring and sweetening syrup up until recently. We have tried to make it easier for us and use one flavor (apple) for most animals. For carnivores, we will prepare something "meaty." We recently purchased FLAVORx because it looked like it would make recipes easier but so far it has been disappointing.

Question: What do you look for in a compounding pharmacist? Are there certain credentials or training that you would recommend?

Ms Rost:

There are a number of organizations that compounding pharmacies can be members of or get accreditation from. Although you don't have to be a member of these organizations to be a quality compounder, it's certainly something to look for: Pharmacy Compounding Accreditation Board (PCAB) for both sterile and nonsterile accreditation, Professional Compounding Centers of America (PCCA), the International Academy of Compounding Pharmacists (IACP), and the United States Pharmacopeia or USP. The USP sets all the guidelines for sterile and nonsterile compounding, and the Food and Drug Agency (FDA) regulates it.

Dr Papich:

The pharmacy you're dealing with should follow the USP to ensure that they are following the standards for compounding. Some pharmacies do and some don't. The USP has very specific standards. The best advice in selecting a pharmacy is to get to know them. Rather than using a large compounding pharmacy, that one could, for example, find on the Internet, I would rather they use a local pharmacy. A practitioner can have frequent communications with a local pharmacy, thereby having a little better assurance that this pharmacy is looking out for them and that they are doing things to help the patient instead of just making money.

Dr Tseng:

We try to look for compounding pharmacies that have a national reputation and are familiar with veterinary drugs and our needs. There is a national Pharmacy Compounding Accreditation Board that certifies pharmacies as meeting safe practices in their compounding facilities.

Dr Petritz:

On the FDA's website, you can find a list of compounding pharmacies nationwide that have been issued warning letters, had inspections, and legal actions against them. (2)

Dr Frank:

I would prefer to use a pharmacy that is accredited by an outside entity such as the PCAB of the Accreditation Commission for Health Care (ACHC). You can also get a sense of how aware the pharmacy is of applicable state, federal, and Drug Enforcement Agency (DEA) rules by reading their website for the multiple restrictions on compounded medications.

Dr Carr:

I have always used the pharmacies that have been used by practices I've worked in.

Dr Mackey:

Of course we want to know that they follow FDA regulations, and it would be ideal to know they carry product liability insurance. But honestly, we initially chose ours based on reputation within the veterinary community.

Question: What do you perceive are the risks of compounded drugs?

Dr Frank:

The most important risks to the patient are ineffective drugs (stability) and delayed response to treatment and recovery as well as contamination (eg, introducing an infectious agent). There are many 'recipes' available to change the form of medications. However, the basic chemistry is not always accounted for such as solubility in water versus alcohol, pH, and other things that affect stability and even distribution in suspension or mixture. Stability can also be affected by storage method, temperature, and light exposure. Using prohibited medications can occur in food animals such as poultry if one is not careful when choosing a medication that is not labeled specifically for the species.

There are also legal issues regarding quality of care and patient treatment. Financial liability to the veterinarian can occur if compounded medications dispensed by a pharmacy causes harm to the pet, and some insurance may not cover this based on the situation. There are also legal issues regarding redispensing of compounded products from pharmacies. Many pharmacies provide a menu of products they encourage veterinarians to purchase and then resell from their hospitals, which is not permitted on the federal level.

Dr Papich:

Unfortunately, some compounding pharmacies make products that are poor quality or highly variable in their content. In other words, in some studies where the drug content of a capsule or suspension has been measured, there has been incredible variability which often exceeded the acceptance criteria for what is allowed by the USP. Although the drug level is supposed to be within 10% of the nominal concentration, some studies have shown that compounded products either exceed that, which could result in a toxicity, or they're under that value, which means they could result in inadequate exposure. The most common problem I have seen is that a drug level is often much lower than it is supposed to be and, therefore, the patient gets a dose that's too low. The other problem is that when you're using an approved product, there are inactive ingredients and vehicles that have been optimized for that particular medication. But when compounding a drug, especially if it's compounded from a bulk chemical substance or "bulk powder," this can often interfere with the oral absorption. In the case of birds, for example, there are some antifungal drugs such as itraconazole that have been compounded from the bulk chemical substance. Even though the drug may have the appropriate potency initially, when it's formulated it may not be well absorbed orally, resulting in inadequate exposure and subtherapeutic levels. The person administering the product thinks that he or she is doing the right thing but, in fact, they're administering an inferior product.

Dr Tseng:

The main risk that I perceive with compounded drugs is that they may not be correctly compounded; that is, they may not be in complete suspension or at an inaccurate concentration. This can certainly affect the efficacy of the treatment regimen. Of course, another important risk is whether or not the compounded drug has been formulated in a sterile manner--obviously, more of an issue with drugs that will be administered parenterally.

Dr Mackey:

Any time I have a compounded drug I wonder if the concentration is correct, is it really stable for as long as it says, and are the ingredients high quality. I worry more about possible contamination. Compounded drugs often have short shelf lives and are expensive, so I worry about the owners trying to use them past the expiration dates.

Dr Carr:

Quality control especially with in-hospital compounding.

Dr Petritz:

Inappropriate compounding can have serious and life-threatening consequences, as was seen in numerous polo ponies in Florida in 2009 which died after receiving a compounded vitamin and mineral supplement that contained a toxic amount of selenium. This unfortunate example highlights the lack of quality control for compounded products.

Compounded medications have several important limitations, including a lack of data demonstrating efficacy, stability (shelf life), purity (presence of potentially harmful ingredients in the medication), potency (actual amount of drug in the formulation), and sterility (important in ophthalmic or injectable products). Stability of a medication can be altered in many ways, some as simple as changing the flavoring, changing the dilution, storage (clear bottle, amber bottle), and refrigeration or lack thereof. There are also usually no studies on the bioequivalence of the drug with the approved drug. Bioequivalence examines the rate and extent of drug absorption for a drug that has an altered form, such as a tablet that is now in a capsule or liquid form. There may be higher or lower peak concentrations or extent of absorption of the compounded medication, which could lead to toxicity or treatment failure.

Ms Rost:

I think the risks in general with compounded drugs is really ensuring that you're asking the right questions of the compounding pharmacist to ensure that what you will receive is a quality product. There are really great compounders out there so 1 don't think that distrusting the entire profession is warranted.

Question: What questions would you recommend to identify a new compounding pharmacist?

Dr Frank:

Ask questions to determine the pharmacy's familiarity with veterinary drugs and species differences. What is their setup for sterile preparation and quality control checks? Does the pharmacy perform independent testing of bulk drugs? Are FDA-approved products used as the drug source? Is the pharmacy compliant with USP standards?

Dr Tseng:

I would ask other veterinarians that treat wildlife/ zoo/exotic species who they've successfully used in the past. I would also ask the compounding pharmacy questions such as what experience they've had with the particular drug in question, what their turnaround time is to get the drug to you, and how quickly the compounded drug will expire.

Ms Rost:

A lot of compounders get their formulations from one of these organizations [PCAB/PCCA/ IACP], so they won't be able to give you the formula that they're using, but they should be able to provide evidence that the formula is safe and effective whether that evidence is primary literature or their own stability studies. What references/ resources do they have that support the compounding of specific drugs? Ask about the stability of their compounds and make sure they follow USP defaults. If there is no evidence saying that a compounded drug is stable for a specific amount of time, then the default is 14 days. If the label says 45 days, what is the evidence for that?

Question: How confident are you that you understand the laws regulating compounds?

Dr Frank:

I follow compounding laws and regulations on a regular basis, but unfortunately they change periodically and both veterinary and pharmacy boards can affect the rules for compounding in each state.

Dr Mackey:

I regularly read articles about compounding law, and I follow what is going on in my state, so I feel pretty confident. That said, every now and then I run into a situation that I am not sure about, and the confidence flies out the window! Luckily there are many resources out there to help you work through questions.

Dr Carr:

So-so. I should be more educated but there isn't one place to go and find the information for my state. I have checked out the pharmacy board and state web sites for specific laws.

Dr Petritz:

In preparation for a recent presentation on compounding in avian practice, I watched a webinar presented by the American Veterinary Medical Association (AVMA) entitled, "Compounding--Are You Playing By the Rules?" I found it very informative, and that webinar, along with additional information about the laws of veterinary compounding, can be accessed on the AVMA website. (3)

Question: What haven't I asked about veterinary compounding in avian practice that you would like to share?

Dr Mackey:

I think when it comes to compounding, we have to carefully evaluate the advantages and disadvantages. It is great to be able to provide a drug in an appropriate volume that is palatable and thereby increasing compliance. At the same time, we have to prepare owners that these drugs can cost significantly more and we don't know that they will work as well. I think it is ideal for practitioners to do their homework as much as possible before they need a medication so there won't be time lost trying to track down a source.

Ms Rost:

Compounding for cost is one of the big issues in veterinary compounding right now, especially with very recent hikes in drug prices. Compounding for cost reasons is technically illegal. If you have a brand new product that is very expensive, compounding that exact replica product just so it's cheaper is illegal and a lot of veterinarians don't know that. Veterinarians may also not be aware that if they get a compound for their practice, they can't then resell that to their clients.

Dr Petritz:

Unfortunately, there is still widespread inappropriate compounding of both veterinary and human medications. Some examples of inappropriate compounding in veterinary medicine include:

* compounding when an FDA-approved formulation is available and appropriate;

* compounding to decrease cost by using bulk ingredients, when an FDA formulation is available and appropriate;

* compounding for food-producing animals; and

* compounding from bulk ingredients when the formulation can be reasonably made from an FDA-approved drug.

There are some published stability studies of commonly used compounded medications in veterinary medicine including enrofloxacin, voriconazole, doxycycline, itraconazole, and metronidazole. Clinicians should be aware of these studies, and ensure that the compounding pharmacies they use follow these published guidelines.

Dr Frank:

There is a push to use transdermal preparations that have no bioavailability studies and based on the particle size are unlikely to be able to pass through the skin barrier unless the skin is significantly compromised. Recovery can occur despite therapy used, and these treatments may be mistakenly thought to contribute to cure.

It should also be noted that some medications can be compounded to improve flavor or acceptance by mixing each dose from stock solution at the time of administration. This can ensure stability and reduce contamination.

If an FDA-approved drug option is available, this should be used first. Cost savings is not an acceptable reason for having a medication compounded.

It is ideal to refer to studies that show safety and efficacy for a specific compounding method and species of animal treated. Unfortunately, there are few studies on commonly used medications, especially in commonly seen species. A study on the injection of a medication in a pigeon is not really applicable to the oral administration of the same medication in a macaw. More studies need to be done on the most common medications and species treated, and also on the stability and sterility of various methods of preparation and storage.

Dr Papich:

I think what sometimes happens, and I might be guilty of this too, is that we often highlight examples of compounding that hasn't gone well. The compounded drug is either of poor quality or the product isn't absorbed. On the other hand, we recognize that compounding is medically necessary, especially for exotic animals. There are good compounding pharmacies out there that do a good job and that have good quality control and good assurances. Sometimes what happens is a couple of bad apples will make the entire profession look bad and that shouldn't happen.

References

(1.) Petritz OA, Guzman DS, Wiebe VJ, Papich MG. Stability of three commonly extemporaneous enrofloxacin suspensions for oral administration to exotic animals. J Am Vet Med Assoc. 2013;243(1):85-90.

(2.) US Food and Drug Administration. Inspections, recalls, and other actions with respect to firms that engage in animal compounding. USFDA Web site. http://www.fda.gov/AnimalVeterinary/ GuidanceComplianceEnforcement/ ComplianceEnforcement/UnapprovedAnimalDrugs/ ucm417562.htm?source=govdelivery&utm_medium= email&utm_source=govdelivery. Updated March 12, 2015. Accessed April 20, 2016.

(3.) American Veterinary Medical Association. Compounding. AVMA Web site, https://www.avma.org/ KB/Resources/Reference/Pages/Compounding.aspx. Accessed April 20, 2016.
Table 1. Types of drugs frequently compounded by roundtable
participants.

                       No. of respondents
                           selecting
Drug category            this category          Examples provided

Antimicrobial                  6            Itraconazole,
                                            amphotericin B,
                                            terbinafine, enrofloxacin
Analgesics                     5            Tramadol, gabapentin
Cardiovascular drugs           4            Enalapril, benazepril
Anti-inflammatories            2            Meloxicam
Hormones                       2            Leuprolide acetate
Nutraceuticals                 1            Milk thistle in lactulose
Anticonvulsants                1            --
Poison antidotes               1            --
Prokinetic agents              1            --
Tranquilizers                  1            --
Electrolytes                   0            --
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Title Annotation:Round Table Discussion
Publication:Journal of Avian Medicine and Surgery
Article Type:Discussion
Date:Jun 1, 2016
Words:3892
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