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FEATURE V E TE R I N A RY I Evaluation of the Most Frequently Prescribed Extemporaneously Compounded Veterinary Medications AT A LARGE INDEPENDENT COMMUNITY PHARMACY Adel H. Karara, BPharm, PhD Ryan Hines, PharmD Zehra Demir, PharmD Bethran Nnorom, PharmD Robert Horsey, RPh Geoffrey Twigg, PharmD, BCACP, CDE www.IJPC.com The authors’ affiliations are: Adel H. Karara, Associate Professor, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland Eastern Shore, Princess Anne, Maryland; Ryan Hines, Pharmacist, Walgreens, Salisbury, Maryland; Zehra Demir, Pharmacist-in-Charge, CVS, Marlton, New Jersey; Bethran Nnorom, Staff Pharmacist, Safeway Pharmacy, Crofton, Maryland; Robert Horsey, Pharmacist, Apple Discount Drugs, Salisbury, Maryland; Geoffrey Twigg, Clinical Pharmacist, Apple Discount Drugs, Salisbury, Maryland. Introduction Although there has been an increase in the number of approved veterinary products on the market, it is still well recognized that extemporaneous drug formulation is essential to provide optimal pharmaceutical care to veterinary patients, especially when medications are not available in the desired dosage form for optimum efficacy. Lack of commercially available products; drug dose adjustment; high cost of finished drug products, especially those for certain neoplastic and immunemediated diseases; ease of administration; and International Journal of Pharmaceutical Compounding Vol. 20 No. 6 | November | December | 2016 461 Veterinary The lack of recent literature data on the most commonly prescribed veterinary preparations was the main reason for this investigation. Thus, the primary objective of this study was to explore the variety of veterinary prescriptions requiring extemporaneous compounding at an independent pharmacy with extensive compounding abilities. A Abstract Extemporaneous drug formulation is essential to provide optimal pharmaceutical care to veterinary patients. The need for this is exacerbated by the fact that commercially produced veterinary-specific products, without a human indication, require specialty veterinary manufacturing facilities and a new animal drug application process to gain marketing approval. This study examined the prescription patterns of extemporaneously compounded veterinary preparations in the compounding department at a large independent community pharmacy. Data was obtained from a total of 1348 prescriptions requiring extemporaneous compounding over the course of a two-year period (2014–2015). A database was constructed and each compounded prescription was allocated to a therapeutic category based on the American Hospital Formulary Service Drug Information. Data analysis showed that the most commonly prescribed preparations belonged to the central nervous system (39%), anti-infective agents (21%), and hormones (12%) therapeutic categories. Overall, suspensions were the most dispensed (47%), extemporaneously compounded dosage forms followed by solutions (28%), and capsules (10%). The majority (88%) of compounded preparations were administered by the oral route. The top three drugs that are compounded for veterinary medicine were (1) potassium bromide oral solution for canine epilepsy, (2) methimazole solution used to treat hyperthyroidism in cats, and (3) metronidazole suspension, an antibiotic for the treatment of diarrhea and other infections in dogs and cats. Remarkably, our findings are in good agreement with previously published survey data on the top drugs that are compounded for veterinary medicine. In the era of personalized medicine, veterinary extemporaneous compounding for specialized needs will continue to play an important role providing optimum therapy for veterinary patients. 462 International Journal of Pharmaceutical Compounding Vol. 20 No. 6 | November | December | 2016 flavor compounding to make medication taste better and enhance compliance are typically the main drivers for veterinary compounding.1 Thus, drug compounding has always been a part of veterinary medicine.2 Very little information is available in the literature regarding the most frequently compounded veterinary drug preparations. A literature search on the topic of “top compounded veterinary preparations” did not yield any hits.3 A regional survey of the subscribers of the International Journal of Pharmaceutical Compounding in 1999 reported on the top ten veterinary compounded preparations, which included potassium bromide capsules, metronidazole suspensions, and methimazole liquid.4 A study by Gargiulo et al,5 based on a survey of 200 randomly selected veterinarians in New Zealand, showed that preparations which were commonly compounded included cyclosporine eye drops, methimazole gels, and potassium bromide solutions. The report acknowledged the importance of the role that compounding plays in providing better therapy for the veterinary patient.5 The lack of recent literature data on the most commonly prescribed veterinary preparations was the main reason for this investigation. Thus, the primary objective of this study was to explore the variety of veterinary prescriptions requiring extemporaneous compounding at an independent pharmacy with extensive compounding abilities, hereinafter referred to as “the retail pharmacy.” www.IJPC.com Veterinary Methods The retail pharmacy has been in operation since 1971. They have performed extemporaneous compounding on an as-needed basis since that time. However, there was a substantial increase in the number of patients serviced in the late 1980s. In 1992, the retail pharmacy joined a professional compounding association (Professional Compounding Centers of America [PCCA]), built a dedicated compounding lab, and was able to dedicate full-time pharmacists’ hours to extemporaneous compounding of medications due to the need of this service in the local community. Today, multiple pharmacists and a full-time pharmacy technician staff the compounding lab attached to the retail pharmacy. Aside from basic equipment, the lab is stocked with a powder safe hood for weighing and manipulation of powder chemicals. To maintain pharmaceutical elegance of creams, ointments, and gels, the retail pharmacy uses an ointment mill and Unguator mixing technology. The pharmacy is also equipped with digital scales, tube sealers, and a convection oven. The compounding records for veterinary preparations over the time interval from January 2014 to December 2015 were entered into a database that included: For the purposes of this study, we evaluated the three most frequently prescribed therapeutic categories, and then listed the most frequently compounded active pharmaceutical ingredient in these individual categories. We were also interested in evaluating the most commonly prescribed dosage forms, route of administration, and animal species. Results Over the study time period, the pharmacy filled about 10,000 total extemporaneously compounded prescriptions when numbers for all patients, human and animal, are considered. That number included a total of 1,348 extemporaneously prepared veterinary prescriptions, including refills, which were entered in the database and were grouped according to AHFS into 13 therapeutic categories. The 1,348 prescriptions came from a total of 801 unique prescriptions with the remainder being made up of ordered refills. Most prescriptions were for canine (33%) and feline (32%) species. Other animal species included: • Guinea pigs •Porcines •Horses • Dosage form • Route of administration • Dosing regimen •Quantity • Patient species • Prescriber name Each compounded prescription in the database was allocated to a therapeutic category based on pharmacologic-therapeutic classification in the American Hospital Formulary Service Drug Information (AHFS).6 The therapeutic categories classified by the AHFS included: • • • • • Antihistamine drugs Anti-inflammatory agents Anti-infective agents Autonomic drugs Blood formation, coagulation, and thrombosis • Cardiovascular drugs • Central nervous system (CNS) agents • Respiratory tract agents • Gastrointestinal drugs • Skin and mucous membrane agents • Hormone and synthetic substitutes •Vitamins • Miscellaneous therapeutic agents www.IJPC.com EMP • Rabbits • Sugar gliders • Rodents • Owls PRO BASIC COMPOUNDING’S NEW STANDARD OF TOP PERFORMANCE EMP (The New E/S) PRO (The New 2100) BASIC (The New B/R) • Automated Lift Arm • 10.1” Touch Display • Compact & Enhanced • Up to 500ml jar sizes • Will Support 2000ml jar • Manual Lift Arm • Touch Panel • Replaceable Lift Arm • Up to 500ml jar sizes • Generates ID Numbers • Barcode Scanner • Generates ID Numbers • Time & Speed Settings • Quick-Lock & Quiet Mix • Time Tracking of Mixes HEALTH ENGINEERING SYSTEMS 2600 Technology Place Norman, OK 73071 405.329.6810 | HEScorp.net International Journal of Pharmaceutical Compounding Vol. 20 No. 6 | November | December | 2016 463 Veterinary FIGURE 1. Therapeutic categories of the most frequently prescribed compounded preparations. Blood Formation, Coagulation, and Thrombosis Antihistamines 1. CNS agents 2. Anti-infective agents 3. Hormone and synthetic substitutes ANTI-INFECTIVE AGENTS Medications belonging to the antiinfective category accounted for 17% of all filled original prescriptions. Prescriptions containing metronidazole were the most commonly prescribed medications, accounting for 6.4% of all filled original prescriptions. This was followed by doxycycline and itraconazole representing 4.2% and 1.9% of prescriptions, respectively. HORMONES AND SYNTHETIC SUBSTITUTES Medications belonging to this category accounted for 12% of all filled original prescriptions. Prescriptions containing methimazole were the most commonly prescribed medications belonging to this category accounting for 10.5% of all filled original prescriptions. Diethylstilbestrol accounted for 1.6% of prescriptions. 464 Phenobarbital Pain Diethylstilbestrol Autonomic Drugs Fluoxetine Miscellaneous Therapeutic Agents CENTRAL NERVOUS SYSTEM AGENTS Medications belonging to the CNS category were by far the most commonly prescribed agents, accounting for 34% of all filled original prescriptions. Liquid prescriptions containing potassium bromide were the most commonly prescribed medication accounting for 20% of all filled original prescriptions. This was followed by diazepam and fluoxetine representing 2.8% and 1.7% of all prescriptions, respectively. Tramadol Vitamins Itraconazole Ursodiol Gastrointestinal Drugs Zonisamide Cardiovascular Drugs Gabapentin Anti-inflammatory Agents Tacrolimus Hormones and Synthetic Substitutes Atenolol Anti-infectives Diazepam Central Nervous System Agents Piroxicam 0 10 20 30 % Total Most Commonly Prescribed Rx 40 Doxycycline Prednisolone Metronidazole Methimazole DOSAGE FORMS Medications belonging to the CNS category Transdermal •Suspensions were by far the most Powder •Syrups Syrup commonly prescribed •Solutions Ophthalmic •Powders agents, accounting for •CapsulesEnema • Ophthalmic solutions Cream 34% of all filled original •Transdermals Capsule •Suppositories prescriptions. Liquid •EnemasSolution Suspension prescriptions containing Overall, the majority of compounded 0 10 20 30 40 50 potassium bromide were preparations (75%) were liquid dosage forms. Suspensions and solutions account- % Total Rx the most commonly ed for 47% and 28% of all dosage forms as illustrated in Figure 2. The top 4 dosage prescribed medication forms compounded were: accounting for 20% of all 1. Suspensions 2.Solutions filled original 3. Capsules prescriptions. 4.Creams Potassium The prescriptions in the database conSuppository tained the following dosage forms: International Journal of Pharmaceutical Compounding Vol. 20 No. 6 | November | December | 2016 f Administration A summary of percentage of the most frequently dispensed extemporaneous prescriptions as a function of main therapeutic categories is displayed in Figure 1. The top three most frequently prescribed products belonged to the following therapeutic categories: Oral Topical Rectal www.IJPC.com 0 P Synthetic Substitutes 0 10 Atenolol Anti-infectives Diazepam Central Nervous System Agents Piroxicam 0 10 20 30 20 30 40 50 Veterinary % Total Rx Doxycycline 40 Prednisolone % Total Most Commonly Prescribed Rx Metronidazole Methimazole FIGURE 3. Route of drug administration. Potassium Route of Administration FIGURE 2. Most frequently prescribed dosage forms. Suppository Transdermal Powder Syrup Ophthalmic 0 Oral 5 10 15 20 25 Topical Rectal Ocular 0 50 Enema 100 150 200 250 300 350 Number of Rx Cream Capsule Solution Discussion Suspension 0 10 20 30 40 50 % Total Rx ROUTE OF DRUG ADMINISTRATION Extemporaneous compounding is historically one of the original methods of the practice of pharmacy. In today’s practice of medicine, most prescriptions can be dispensed from commercially available products. Extemporaneous compounding is a niche role that some pharmacies fulfill. However, with the needs of special Route of Administration Orally administered dosage forms constituted the majority of compounded prescriptions as depicted in Figure 3, with topical, rectal, and ocular accounting for a small fraction of Oral total prescriptions. Topical Rectal TOP COMPOUNDED DRUG AGENTS Ocular The top three drug agents that were 0 50 100 150 compounded for veterinary medicine were: ARL Bio Pharma, Inc. 200 Number of Rx 1. Potassium bromide oral solution to treat canine epilepsy 2. Methimazole solution to treat hyperthyroidism in cats 3. Metronidazole suspension, an antibiotic for treatment of diarrhea and other infections in dogs and cats as seen in Figure 4 Table 1 shows a comparison of the top 10 veterinary compounded preparations based on a survey conducted in 19994 and our current data. Although almost fifteen years separate the two surveys, examination of the data show remarkable similarities, especially in the top three veterinary compounded preparations. www.IJPC.com 250 300 30 Percent of Most Frequently Compounded Drug Agents 350 (800) 393-1595 | www.arlok.com A high-quality laboratory for compounding pharmacies and outsourcing facilities. Analytical and Microbiological Testing Potency Determination Sterility and Endotoxin Stability (BUD) Studies Raw Material Testing Particulate Matter Microbial Identification Preservative Effectiveness non-cGMP and cGMP services available International Journal of Pharmaceutical Compounding Vol. 20 No. 6 | November | December | 2016 465 Veterinary Blood Formation, such as hospice, pediatrics, and veterinary patients, populations oagulation, and Thrombosis along with the prescribers desire to tailor medication regimens to Antihistamines specific patient needs, extemporaneous compounding fills a major gap inVitamins the care of these patients.7 Extemporaneous compounding is emerging as a specialized area of pharmacy practice with the Pain emphasis on personalized and patient-centered health care. Sherr Autonomic Drugs and Karara have noted that it would be important for compounding Miscellaneous to explore opportunities for marketing their services pharmacies Therapeutic Agents to veterinary clinics in order to provide optimum care for the Gastrointestinal Drugs veterinary patient.8 In theDrugs present study, the total number of veterinary prescripCardiovascular tions (1348) provided enough volume to examine the prescription Anti-inflammatory Agents patterns of extemporaneously compounded veterinary medications Hormones at a largeand independent community pharmacy. Remarkably, our Synthetic Substitutes findings are in agreement with previously published survey data Anti-infectives on the top drugs that are compounded for veterinary medicine.4 that the top three drugs that were compounded for tral Nervous Davis System reported Agents veterinary medicine were4: 0 10 20 30 1. Potassium bromide % Total Most Commonly Prescribed Rx 2. Metronidazole suspension 3. Methimazole oral liquid 40 FIGURE 4. Most frequently compounded drug agents. Tramadol Phenobarbital Diethylstilbestrol Fluoxetine Itraconazole Ursodiol Zonisamide Gabapentin Tacrolimus Atenolol Diazepam Piroxicam Doxycycline Prednisolone Metronidazole Methimazole This is in agreement with our data. It was interesting to note the similarities as well as the differences in the older survey and our data. There was very little change in the majority of the commonly Suppository prescribed drugs. The top three drugs in both lists contained: Potassium 0 5 10 15 20 25 30 Percent of Most Frequently Compounded Drug Agents Transdermal 1. Potassium bromide (for seizure prevention) 2. Methimazole (for hyperthyroidism) Syrup 3. Metronidazole (for bacterial infections) Powder has gone up along with concerns of bone marrow suppression, and hepatic monitoring requirement has caused this medication to be a last-line therapy. It is also interesting to note that no pain medications made the 1999 list, but two medications for pain—gabapentin and piroxicam—were included in our results. Piroxicam also has an added indication in canine patients for bladder cancer. Ophthalmic Route of Administration The use of diethylstilbestrol, commonly used for urinary Enema incontinence in spayed dogs, is no longer prescribed as often as Cream it had been; the amount of side effects and blood-work monitorCapsule ing required has caused the drug to fall out of favor. Cyclosporine used as an eye drop can no Solution longer be compounded due to Suspension TABLE 1. Comparison of the Top Ten Veterinary Compounded Preparations. a usage patent. Since the Davis 4 publication, this 10 chemical is 0 20 40 DATA PROVIDED 50 30 IN DAVIS J. COMPOUNDING FOR DATA FROM THIS 2014now available commercially. % Total Rx RANKING CREATURES: WHAT WORKS. IJPC 1999; 3(3): 182–185 2015 STUDY* The price of the commercial 1 Potassium bromide capsules Potassium bromide product and the lack of pre2 Metronidazole suspension (various strengths) Methimazole scription insurance for most 3 Methimazole 5-, 10-, 100-mg/mL oral liquid Metronidazole animals make this an impracti4 Diethylstilbestrol 0.5-mg, 1-mg, 2-mg, 3-mg, 5-mg capsules Prednisolone cal option for many pet owners. 5 Potassium bromide solution Doxycycline In place of cyclosporine, we 6 Cyclosporine 2% ophthalmic solution Piroxicam now typically use tacrolimus. 7 Prednisone 0.5-, 1-, 5-, 10-mg/mL oral liquid Diazepam Chloramphenicol, an inexpen8 Amitriptyline 5to 100-mg/mL oral liquid Atenolol sive broad spectrum antibiotic, 9 Chloramphenicol 150-mg/mL oral suspension Tacrolimus is not used as often as it was Oral 10 Protamine zinc insulin, 10 to 100 units/mL Gabapentin back in 1999. Since that study,4 the rate Topical of antibiotic resistance *Active ingredients in different dosage forms and strengths. 466 Rectal Ocular International Journal of Pharmaceutical Compounding |150 2016 200 Vol. 20 No. 60| November 50 | December 100 250 300 350 www.IJPC.com Veterinary A report by an independent pharmacy shows that top compounded medications for companion animals were: aminopentamide, cisapride, cyclosporine, diethylstilbestrol, methimazole, metronidazole, tacrolimus and trilostane.9 Due to the limitations in data collections, not all prescriptions contained the species of the animal that was being treated. When this information was available, canines and felines made up the majority of the animals. Some of the other animals that were serviced by the pharmacy were: • Guinea pigs • Sugar gliders •Birds • Chinchillas • Rodents Limitations to the findings of our study related to the fact that it was conducted at one site. While study findings are similar to that of the cited 1999 study,4 it may not be representative of prescribing habits in other locations. Also, the pharmacy where the study was conducted has invested considerable resources on the infrastructure of the compounding lab and on educating the public and prescribers on the use and availability of extemporaneous-prepared formulations. This may not be typical for other community pharmacies that provide compounded drug formulations to patients. We are hopeful that this report would stimulate more research into the unmet compounding needs in the area of veterinary drug compounding. Conclusions Veterinary prescriptions belonging to the therapeutic categories of CNS agents, anti-infective agents, and hormone and synthetic substitutes were the three most commonly prepared extemporaneous medications. Overall, the most dispensed extemporaneously compounded dosage forms were suspensions, solutions, and capsules. Canine and feline patients were the most treated patients seen by the pharmacy. Overall, veterinary compounding is a large part of the compounding pharmacy’s workflow, making up approximately 15% of all the compounding prescriptions dispensed. www.IJPC.com Acknowledgment The authors would like to acknowledge Ms. Emanga Ekinde and Ms. Mineille Gakuu both Student Pharmacists of the Class of 2016 for their help with the prescription database. References SUGAR GLIDER 1.Karara AH. (2016). FDA draft guidance on compounding animal drugs from bulk drug substances: A commentary. AAPS Open 2016; 2: 5. 2. Papich MG. Drug compounding for veterinary patients. AAPS J 2005; 7(2): E281–E287. 3. PubMed Literature Search. National Center for Biotechnology Information. Top Compounded Veterinary Preparations. [NCBI Website.] Available at: www.ncbi.nlm.nih.gov/pubmed/?ter m=Top+compounded+veterinary+preparations accessed. Accessed on February 5, 2016. 4. Davis J. Compounding for creatures: What works. IJPC 1999; 3(3): 182–185. 5. Gargiulo DA, Chemal C, Joda L et al. Extemporaneous compounding in veterinary practice: A New Zealand prespective. N Z Vet J 2013; 61(6): 311–315. 6. McEvoy GK, ed. AHFS Pharmacologic—Therapeutic Classification. In: American Hospital Formulary Service Drug Information. Bethesda, MD: ASHP; 2007. 7. Nahata MC, Allen LV Jr. Extemporaneous drug formulations. Clin Ther 2008; 30(11): 2112–2119. 8. Sherr Z, Karara AH. Evaluation of the most frequently prescribed extemporaneously ccompounded medications in a rural setting: A case study from the Delmarva Peninsula. IJPC 2014; 18(6): 462–468. 9. Scully P. Wedgewood Pharmacy. Top 15 Compounded Veterinary Medications for Companion Animals and Horses: Veterinary Compounded Medications that May be Prescribed for Companion Animals. [Wedgewood Pharmacy Website.] June 27, 2011. Available at: www.wedgewoodpetrx.com/blog/posts/ top-15-compounded-veterinary-medications-forcompanion-animals-and-horses.html. Accessed February 5, 2016. Address correspondence to Adel H. Karara, B Pharm, PhD, Associate Professor, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland Eastern Shore, 11868 Academic Oval, Princess Anne, MD 21853. E-mail: [email protected] International Journal of Pharmaceutical Compounding Vol. 20 No. 6 | November | December | 2016 467