Drug compounding: Balancing risks versus rewards (Proceedings)

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Drug companies cannot supply labeled drug products to treat every condition in every species, and veterinarians often turn to extra-label drug use to fill these unmet therapeutic needs.

Veterinarians are required to treat multiple species of animals of vastly different body sizes and physiological needs. Drug companies cannot supply labeled drug products to treat every condition in every species, and veterinarians often turn to extra-label drug use (ELDU) to fill these unmet therapeutic needs. A special form of ELDU is compounding medications. The best definition I found of compounding is probably the simplest: combining 2 or more ingredients, at least one of which is a drug, to create a final product in an appropriate form for dosing. Although compounding drugs has been practiced for centuries, it has recently sparked debate between veterinarians, pharmacists, drug companies, and regulatory agencies.

Why use compounded medications?

There are several valid reasons why veterinarians may use a compounded drug:

1. Access to a product that is not commercially available.

• Examples include cisapride, a gastric prokinetic drug often used for constipated cats with megacolon, or KBr for the management of canine epilepsy. This requires the use of bulk drug ingredients, which is technically illegal in the USA. However, the FDA uses discretion if it is to make a life-saving therapeutic drug (such as antidotes for toxic compounds in food animals).

2. Formulation of a more appropriate size/concentration of an existing drug to allow for better dosing accuracy in small patients.

• This may be diluting an oral liquid or syrup medication, or producing smaller concentration pills or capsules from a larger oral drug.

3. Improve client compliance:

• Making an oral medication more palatable for finicky dogs and cats, or creating a non-oral preparation (eg. transdermal gel) of drugs for owners who cannot pill their pet.

Notice that cost is not a valid reason to use a compounded drug!

Although compounded medications can be beneficial for our patients and their owners, regulatory agencies in the United States and Canada have recently raised some concerns about compounded products. The FDA's general rules on compounded medications include:

• They are used to fill an unmet therapeutic need or to reduce animal suffering

• They do not cause harm to treated animals

• They don't result in therapeutic failure

• They do not result in violative drug residues in food animals

Specific concerns regarding compounded medications include

Purity Does the compounded product contain only the correct drug(s), and nothing else? This was well illustrated by a recent Canadian example, where compounded "florfenicol" from a bulk source destined for large animals actually contained choramphenicol! (which is banned for use in food animals due to potential for residues causing aplastic anemia in humans). This would be illegal in the USA (and it should be in Canada, too) because a compounded drug cannot be made from a bulk source if commercial preparations are available, especially when used in food animals. In another example, allergic reactions at injection sites in horses may have been caused by impure compounded forms of ketoprofen, amikacin, and boldenone. Be sure your compounding pharmacist can PROVE the drug in the compounded product is the right one.

Potency Does the compounded medication actually contain the amount of drug it says it does? Drug manufacturer's products must be within ±5% of the concentration on the label. An evaluation of 19 compounded meloxicam formulations from 6 Canadian compounding pharmacies found that 12/19 didn't contain the concentration specified on the label (potency ranged from 37-132% of the label concentration). An NC State lab examined a 100 mg itraconazole capsule produced by a compounding pharmacy, and found that it contained no trace of itraconazole! When you use compounded medications, do you have a proper chemical analysis showing the drug concentration in the compounded final product is correct?

Stability The expiration date on date on approved pharmaceuticals is based on trials demonstrating the amount of time a compound is chemically stable and its formulation remains consistent. However, changing the formulation can drastically alter the stability. Examples include:

• Hydrolysis can occur when a liquid is added to a product to create a solution or suspension form (eg. -lactams). If a drug comes in a blister pack or moisture-proof barrier, it shouldn't be mixed in liquid!

• Oxidation due to light or O2 exposure may inactivate a drug. Oxidation can be seen if the color of a drug changes to pink or amber. If the drug is originally in a light-protected container, it is probably inactivated by light!

• Precipitates may form in a drug solution, and they can't always be re-suspended by vigorous shaking. This can occur when diluting a drug already dissolved in organic solvents (like diazepam in propylene glycol) with an aqueous solution like saline or LRS.

• Although fluoroquinolones are compatible and stable with most mixtures, there are some exceptions. Orbifloxacin mixed in Lixotinic becomes less stable over time, thought to be due to drug binding with iron. Enrofloxacin may become chelated with aluminum when combined with antacids or sucralfate.

• A compounded suspension may not remain homogenous over time, leading to variable drug concentration as it "settles out".

Ask your compounding pharmacist if stability trials have been performed on the compounded product. As a general rule, a compounded drug should have an expiry date of no more than 25% of the time remaining on the expiry date of the original product. If you are ordering from a compounding pharmacy, you likely don't know the original expiry date—but in general compounded products shouldn't have an expiry date longer than one month.

Bioavailability Changing the formulation of a drug can alter its absorption and bioavailability. Compounded drugs that have been studied include:

• Omeprazole—a compounded suspension formulation was ineffective it treating gastric ulcers in Thoroughbred racehorses, whereas the commercial paste formulation was effective.

• Amitriptyline and buspirone—transdermal absorption in cats was negligible compared to oral absorption.

• Glipizide--transdermal bioavailability is only 4-30% of oral bioavailability.

• Methimazole—transdermal gels are very popular for treating hyperthyroid cats. Although oral treatment results in lower mean T4 concentration after 2 weeks than transdermal gels, some cats are effectively treated with gels. Transdermal methimazole may also result in lower GI side effects than oral treatment.

• Dexamethasone—negligible absorption in cats when applied in transdermal gels.

Note: many compounding pharmacies promote the use of PLO (pluronic and lecithin organogel) in transdermal gels as a means of increasing absorption. However, no commercial transdermal formulations use this method, and all of the examples above used PLO formulations with minor (at best) success. Just because a drug is formulated into a gel doesn't mean it works!

How to choose which medication to prescribe

Guidelines for using compounded medication are available from numerous sources, including the FDA, American and Canadian Veterinary Medical Associations, pharmaceutical companies, and pharmacy associations. I won't go through them all, but here is a quick chart that helps guide your medication decision-making process. Choose a drug from the first available level:

1. Approved veterinary drug at label recommendations

2. Approved veterinary drug: extra-label use (ELDU)

3. Approved human drug (ELDU)

4. Compounded product: from approved veterinary drug (ELDU)

5. Compounded product: from approved human drug (ELDU)

6. Compounded product: from bulk source (ELDU)

(Illegal if commercial formulation available, if not available it's still questionable!)

Other points I found interesting

• Although there is some art to compounding medications, there is a lot of science & technique involved as well. If you are using compounded medications in your clinic, I strongly recommend they come from a licensed, reputable compounding pharmacy. Having a mortar & pestle does not make your clinic an appropriate compounding facility!

• Because compounding is meant to provide a patient with a customized medication to meet its own unique needs, it should only be used when a valid veterinarian-client-patient relationship exists (it can't be "customized" if you prescribe it for every patient, or for a patient you don't even know!)

• It is imperative that clients give informed written consent before prescribed a compounded medication. Like any other treatment protocol, owners must be warned of the risks involved before using a compounded drug. However, it must also be clearly understood by the owner that this is not a government-approved product. It also cannot be described as a "generic" version of a brand name drug—they are not the same thing.

• You as the veterinarian are liable for the product's quality, safety, and efficacy, even if you didn't compound the drug yourself. Unlike the situation when using an approved drug, if an adverse drug reaction or quality control issue arises you will receive no support from the pharmaceutical company.

References

CVMA. Canadian Veterinary Medical Association Guidelines for the Legitimate Use of Compounded Drugs in Veterinary Practice. https://canadianveterinarians.net/Documents/Resources/Files/327_Compounding_Guidelines_E_Final.pdf (accessed September 2006), 2005.

Davidson G. The compounding controversy: what veterinarians should know to protect themselves and their patients. J Am Anim Hosp Assoc 2003;39:13-17.

FDA. Compliance Policy Guide Sec. 608.400 - Compounding of Drugs for Use in Animals. www.fda.gov/ora/compliance.ref/cpg/cpgvet/cpg608-400.html (accessed September 2006), 2003.

Haskell SR, Payne M, Webb A, et al. Antidotes in food animal practice. J Am Vet Med Assoc 2005;226:884-887.

Hawkins MG, Karriker MJ, Wiebe V, et al. Drug distribution and stability in extemporaneous preparations of meloxicam and carprofen after dilution and suspension at two storage temperatures. J Am Vet Med Assoc 2006;229:968-974.

Ingwersen W. Your client credibility: are your pharmacy practices helping or hindering? The Canadian veterinary journal 2004;45:695-699.

Mealey K, Peck,KE, Bennett,BS, Sellon,RK, Swinney,GR, Melzer,K, Gokhale,SA, Krone,TM,. Systemic absorption of amitriptyline and buspirone after oral and. Journal of veterinary internal medicine 2004;18:43-46.

Nieto JE, Spier S, Pipers FS, et al. Comparison of paste and suspension formulations of omeprazole in the healing of gastric ulcers in racehorses in active training. J Am Vet Med Assoc 2002;221:1139-1143.

Papich MG. Drug compounding for veterinary patients. AAPS J 2005;7:E281-287.

Sartor LL, Trepanier LA, Kroll MM, et al. Efficacy and safety of transdermal methimazole in the treatment of cats with hyperthyroidism. J Vet Intern Med 2004;18:651-655.

Boothe DM. Veterinary compounding in small animals: a clinical pharmacologist's perspective. Vet Clin North Am Small Anim Pract. 2006; 36(5): 1129-1173.

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