Pharmacologic studies help DVMs dispel commonly held myths
Q: Could you address some of the common misconceptions in the market?
A: Dr. Mark G. Papich at the 2006 American College of Veterinary Internal Medicine Forum in Louisville, Ky., gave a lecture on myths and misconceptions in small animal therapeutics. Some relevant points in this lecture are provided here.
In small animal therapeutics there are many legends, outdated treatments, misconceptions and myths that persist. Data is now available through pharmacologic studies to dispel many of these old thoughts and concepts.Are generic drugs as effective as proprietary drugs?
It is a common misconception that generic drugs are inferior or less effective than proprietary drugs. For a generic drug to be registered by the Food and Drug Administration (FDA), it must meet criteria for bio-equivalence. Drugs are considered therapeutic equivalents if they are pharmaceutical equivalents and if they can be expected to have the same clinical effect and safety profile when administered to patients under the conditions specified in the labeling. This does not necessarily mean that the generic formulation of a drug has been tested in therapeutic trials. It simply means that when equivalent doses are administered as the proprietary drug formulation (also known as the pioneer drug or innovator drug), the blood concentrations are equivalent based on the shape and profile of a concentration versus time curve. If a generic drug meets these criteria, one assumes that if plasma concentrations of a drug are equivalent, the therapeutic response also must be equivalent. There are no instances documented in veterinary medicine in which an FDA-approved drug has not been equivalent to the proprietary drug. Therefore, a claim that generic drugs are not effective is unproven. However, veterinarians recognize that among generic drug formulations, excipients, vehicles, colors, packing, tablet shape and release characteristics can vary. It is theoretically possible that differences in these additional ingredients could change the therapeutic response. Because there are few generic drugs registered for veterinary medicine, most generic drugs used in animals are human drugs. Even though bioequivalence may have been demonstrated in people, there is no assurance that the pattern of absorption, metabolism and excretion would be similar in animals.
Are compounded drugs equivalent to brand-name drugs?
Compounding is the practice of modifying a dose form in order to facilitate administration to a patient. Compounding can be a therapeutic necessity because veterinarians lack the availability of medications to treat the variety of diseases in animals. For example, human dose formulations must be modified to administer to a dog, cat or exotic animal. Sometimes compounding is performed to ease administration, mask a bitter taste or accommodate an animal's small size. Compounding is allowed by federal law, provided that it is performed on a patient-by-patient basis and other restrictions are met. The FDA Center for Veterinary Medicine restricts compounding from bulk chemicals containing the active pharmaceutical ingredient, especially if it is performed on a large scale.
Compounded formulations may provide an equivalent therapeutic response to a proprietary formulation in many instances. However, there may be problems with solubility, stability and potency for some drugs. The inactive ingredients and excipients added to drug formulations are done to ensure the stability of the drug, provide an optimum chemical environment, pH, or increase the ease of packaging or handling. Adding other chemicals, flavorings, vehicles or interfering with protective coatings of tablets in the course of compounding may interfere with the stability of the drug, decreasing its potency, oral absorption and efficacy. The most-common interaction is that from a change in pH. Drugs known to be compromised when compounded for animals include omeprazole, fluoroquinolone antimicrobials, diazepam, antifungal drugs (e.g., itraconazole) and poorly soluble basic drugs.
There may be clues that compounding has affected drug quality, purity or potency. Oxidation is often visible through a color change (color change to pink or amber for example). 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 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 accumulated moisture and may have lost potency.
Do transdermal gels really work?
To meet the growing demands for more transdermal medications for animals, compounding pharmacies have prepared existing drugs (both human and veterinary drugs) into transdermal formulations. Most drugs cannot be absorbed across the skin without some enhancement. Their lipophilicity or solubility characteristics otherwise prevent the drug from penetrating the skin. Therefore, veterinary compounding pharmacies have mixed drugs with penetration enhancers (PE) to facilitate transdermal absorption. The most popular PE used by veterinary pharmacists is pleuronic lecithin organogel (PLO), which is lecithin (derived from eggs or soybeans) mixed with isopropyl palmitate and a poloxamer (pluronic). The ingredients in PLO act as surfactants, emulsifiers and solubilizing agents. There is little data available to suggest that drugs applied in a PLO vehicle are actually absorbed systemically in animals. Most published reports of transdermal application of drugs to cats showed that absorption was incomplete, nonexistent or highly inconsistent. Drugs examined so far have included glipizide, dexamethasone, buspirone, amitriptyline, fentanyl, morphine, fluoxetine, buspirone, morphine, fentanyl, enrofloxacin, diltiazem and methimazole. Drug absorption through the skin is actually more challenging than expected. The barriers of stratum corneum, hair and first-pass metabolism limit this route. In addition, some drugs may not be soluble or compatible in a transdermal vehicle. Many drugs are not potent enough to be delivered in the small volume (often 0.1 ml) required for practical transdermal therapy.