Drug compounding: issues affecting safety and efficacy (Proceedings)

The use of compounded products in veterinary medicine is a common practice due to the lack of approved veterinary drugs and convenient, palatable administration forms. There is no regulation of pharmacies that compound drugs for veterinary use. There are no standard formulas available to pharmacies to guide them on the optimum methods for ensuring a quality product. Variation in product potency and stability is rarely, if ever tested. Additionally, the effect of storage conditions on the stability of these drugs in aqueous vehicles or in syrups has not been reported. An understanding of the rules and regulations, as well as the pharmacologic principles surrounding compounding practices, is necessary in order to ensure that the safest, most effective method of treatment is being used.

Why do we worry about compounded preparations?

Compounded drugs have not been evaluated by the FDA approval process for safety, efficacy, stability, potency and consistency of manufacturing. Therefore, you should not assume compounded drugs are consistent from one batch to another, contain the stated amount of drug substance, or are safe and efficacious for the intended use.

Some compounded drug formulations can present problems if the safety and potency of the compounded product have not been considered. Tablets that must be crushed or broken to deliver a smaller dose size to dogs or cats may be unpalatable for oral use in animals. When drugs are administered to cats, either a portion of a tablet must be given, or the drug is reformulated into a capsule. Because ill cats are usually anorectic and because cats generally do not drink water frequently, solid dose forms have become trapped in the esophagus of cats. The latter problem was documented in two studies in which capsules were orally administered to cats. The location of the entrapment of capsules is particularly disturbing because some medications given to cats such as doxycycline, tetracycline, propranolol, iron supplements, and bromide are known to cause esophageal lesions in experimental cats.

The vehicle used for compounding may affect the drug in several ways. In some instances, the only change is a slight alteration of pH. But, according to the USP-NF, "... a pH change of only one unit could decrease drug stability by a factor of ten or greater." This change in stability may be secondary to stearic rearrangement or oxidation of the compound. Compounding often involves tablets being crushed, or capsules being reformulated, to make a more convenient and palatable oral dosage form. During this process, protective coatings are disrupted, which exposes the drug to the pH of the vehicle.

Storage temperature also can affect drug stability in compounded formulations. Package inserts for drug products contain strict recommendations for storage conditions, and the labels for compounded formulations often state specific storage temperatures. Accelerated degradation can be seen when drugs are exposed for short periods of time to temperatures of 40-60°C. These are similar to temperatures that the drugs can be exposed to if they are improperly stored in barns or inside vehicles. Both metronidazole and chloramphenical have shown an accelerated degradation at high temperatures when dissolved in aqueous vehicles. Other drugs, are degraded at lower temperatures (<5°C) or during the process of freezing and thawing. Compounded products stored in barns during the winter months may experience freezing temperatures and undergo daily freeze-thaw cycles during the course of treatment which may also adversely affect the stability of the drugs. Ora-Sweet may precipitate in cold temperatures, which will adversely affect drug solubility.

Drugs formulated as acids—such as the hydrochloride form of basic drugs—are designed to maintain their solubility in aqueous solutions. However, when these formulations are mixed with drugs that are basic, or are added to basic vehicles, drug precipitation may occur.

Several drugs are not soluble in aqueous vehicles. Therefore they are dissolved in organic solvents (propylene or ethylene glycol for example), or alcohols. These are notoriously unpalatable to some animals, particularly cats. However, if these formulations are diluted in aqueous fluids, or aqueous flavorings added, precipitation may occur. When these are stored at home by the pet owner, precipitation of the drug to the bottom of the container results in the dosing of a dilute mixture when the container is sampled from the top and a highly concentrated mixture when the container is sampled from the bottom (assuming that the precipitate at the bottom can be re-suspended). This also may be observed when mixing some drugs in aqueous fluids. For example if diazepam solution (which contains propylene glycol and alcohols) is diluted in saline solution or lactated Ringer's solution, precipitation occurs.

Addition of a water-based solution to a product to create a liquid solution or a suspension results in the hydrolysis of certain compounds (e.g., β-lactams and esters). Some drugs undergo epimerization (steric rearrangement) when exposed to a pH range higher than what is optimum for the drug (for example this occurs to tetracycline when exposed to a pH higher than 3). Other drugs are oxidized, a reaction catalyzed by exposure to a high pH, rendering the drug inactive. Drugs most likely to be subject to oxidation are those with a hydroxyl group bonded to an aromatic ring structure.

Veterinarians and pharmacists are obligated to be cognizant of the potential for interactions and interference with stability. Oxidation is often visible through a color change (e.g., color change to pink or amber). Loss of solubility may be observed through precipitation. Some drugs are prone to hydrolysis from moisture. A rule-of-thumb for veterinarians is that if a drug is packaged in blister packs or in moisture proof barrier, it is probably subject to loss of stability and potency if mixed with aqueous vehicles. If compounded formulations of solid dose forms show cracking, "caking", or swelling, the formulation has probably acquired moisture and may have lost potency. Another rule-of-thumb is that if the original packaging of a drug is in a light-protected or amber container, it is probably prone to inactivation by light. Vitamins, cardiovascular drugs, and phenothiazines are labile to oxidation from light during compounding. Also, as a general rule, if an antibiotic is available in a powder that must be reconstituted in a vial or in an oral dispensing bottle prior to administration, it should not be mixed with other drugs.

Compounding of drugs has previously been shown to adversely affect the efficacy of that drug. For example, a Merial study showed that compounded formulations of omeprazole may have as little as 6% of the actual intended amount of drug. Additionally, compounded omeprazole is usually not effective in treating horses with gastric ulceration. Fluoroquinolone concentrations may be decreased by as much as 50% when mixed with vitamin and mineral supplements, such as Lixotinic. The use of unstable compounded products may result in sub-therapeutic concentrations of drugs being delivered, leading to treatment failures, excess cost, and in some cases, death of the patient.

Antifungal drugs also are subject to instability. Itraconazole is frequently compounded from bulk drugs or the proprietary capsules. However, during compounding, inactivation may occur. Itraconazole may adsorb to plastic and glassware, decreasing product drug concentrations. Recently in our laboratory, we have analyzed compounded capsules of itraconazole that were obtained from referring veterinarians. We found that the concentrations of itraconazole from compounded formulations varied from 0% to 100% of the intended potency. Powdered bulk itraconazole is practically insoluble in aqueous solutions and has poor solubility when administered orally. We have analyzed plasma samples from horses and cats given compounded itraconazole products and found that there was no detectable drug in the samples, regardless of the drug concentration in the compounded product.

Aminoglycoside antibiotics (gentamicin, tobramycin, and kanamycin) are inactivated when admixed with other antibiotics, particularly beta-lactams. This interaction is greatest with carbenicillin, followed by ticarcillin, penicillin G, and ampicillin. Loss of potency by as much as 50% can occur within 4 to 6 hours. This interaction is a potential problem when antibiotic mixtures are prepared and dispensed for use several hours later. This interaction does not occur at therapeutic concentrations within the patient because the drugs are diluted in plasma and body fluids.

Transdermal products are also compounded for veterinary use. Frequently, these are drugs combined with a penetration enhancer to increase drug absorption across the skin. The most common of these to be used is pleuronic lecithin organogel (PLO). These formulations have been studied in some veterinary species. Amitriptyline and buspirone, dexamethasone, morphine, fentanyl and enrofloxacin show minimal absorption following topical applications of PLO gels. Fluoxetine absorption was approximately 10% when applied topically, compared to oral administration. Glipizide transdermal bioavailability was between 4 and 30% in cats. Methimazole shows some promise for use with this method, as a clinical effect was noted in cats with hyperthyroidism treated topically, despite low to undetectable serum concentrations of the drug. Fewer GI side effects were noted with this route of administration, compared to oral administration.

What are the regulations regarding compounded products?

There are several federal regulations that must be followed in order for compounded preparations to be used in equine patients:

• A valid Veterinarian-Client-Patient relationship must exist

• There must be no available drug labeled for treatment of the disease in that species

• Product must be made from an FDA-approved drug

• The product must be compounded by a veterinarian or by a pharmacist for a veterinarian

• The product must be safe and effective

• The amount of product compounded must be commensurate with the need of the animal

• Veterinarians must comply with all aspects of extralabel drug usage, including record-keeping and labeling requirements

• All relevant state laws must be followed

What are the potential consequences of using compounded drugs?

Veterinarians that use compounded formulations and do not comply with federal regulations are subject to FDA penalties, State Board actions, lawsuits by clients, as well as charges of negligence, breach of contract and fraud. More importantly, you may be using a drug that is not effective for treating your patients. In some instances, compounded products have even been implicated in the death of the patient.

In order to minimize the risk of these consequences, the following practices should be instituted:

• Ensure that the pharmacy you are using is licensed to practice in the state in which you practice

• Educate yourself and others in the practice regarding the regulations concerning compounded medications

• Do not associate with firms that offer trademarked brands in the literature to promote 'look-alike' compounded products

• Contact your state's pharmacy boards regarding the re-selling of compounded products

• Ask the pharmacist about the product used to compound the formulation, the expiration dates and how they were calculated, how the product formulation was determined, and how sterility of the product can be guaranteed

• Inform the owner of the risks and benefits associated with compounded products.

• Whenever possible, use FDA-approved products.