Insights into Current Veterinary Pharmaceutics for Companion Animals in Japan: A Study Based on Data from the Veterinary Drug Side Effect Database

Abstract

In veterinary medicine, various drugs are used on a daily basis. Using inappropriate medications poses health hazards to companion animals and humans; thus, assessing adverse events in veterinary medicine has great social significance but remains an untapped area of research. In this study, to promote the appropriate use of veterinary drugs and clarify common pharmaceutical issues in Japanese veterinary medicine, we analyzed information in the Veterinary Drug Side Effects Database (National Veterinary Assay Laboratory of the Ministry of Agriculture, Forestry and Fisheries, Japan). We found that the number of reports has been increasing annually, including those on high-risk drugs, molecular-targeted drugs, and antibody-based drugs. The details of the reports were similar to those from the United States, including the misadministration of veterinary drugs to humans, improper drug management, and re-administering drugs with a history of side effects. Furthermore, 46.50% of all reports mentioned the administration of one or more drugs, with the highest number of concomitant drugs being 10. In addition, 37.78% of all reports described the use of drugs in manners deviating from the intended use indicated in the package insert. Therefore, to avoid adverse events, pharmacists may have to be involved in dispensing and aseptically preparing veterinary medicines and providing drug information and medication guidance. To optimize pharmacotherapy for ill companion animals, “veterinary pharmacy” and “veterinary medicine pharmacy” must be developed in line with clinical situations in Japan, while considering knowledge from countries that are advanced in terms of veterinary medicine.

INTRODUCTION

In 2020, approximately 18133000 companion animals were being raised in Japan,¹⁾ exceeding the population of Japanese children younger than 15 years of age.²⁾ This situation reflects the increased longevity of pets owing to advancements in veterinary medicine and the increasing incorporation of pets into families. Similar to humans, pets develop various diseases such as cancer and diabetes with increasing life span; thus, an increasing social need exists for more advanced veterinary medicine.³⁾

The global market for animal health is expected to expand further; domestic sales of veterinary drugs in 2019 totaled approximately 130 billion yen.⁴⁾ Various medicines are used for animals on a daily basis, including those that humans have little experience with, such as molecular-targeted drugs. Indeed, improper use of medicines worsens not only the treatment outcome of the ill animals, but it may also adversely affect human health. Therefore, it is of great social significance to determine drug-related adverse events in veterinary medicine.

Pharmacists already play an important part in veterinary medicine in other countries.⁵⁾ For example, the U.S. Food and Drug Administration (FDA) collects information on adverse events and medical malpractice pertaining to drugs used in veterinary medicine, and the utilization of such information is progressing.⁶⁾ In Japan, a publicly available database hosting information regarding reported adverse effects of veterinary drugs has been established.⁷⁾ However, there are only a few reports on the involvement of pharmacists in veterinary medicine or pharmaceutical research in Japan. Therefore, in this study, we analyzed the side effects of veterinary drugs in Japan and compared them with those reported in the United States.

MATERIALS AND METHODS

Data Collection and Characterization

Of 3874 reports, spanning from February 2002 to December 2020, available in the Veterinary Drug Side Effects Database of the Japanese Ministry of Agriculture, Forestry and Fisheries,⁷⁾ 1438 reports on drugs (excluding vaccines and those related to industrial animals) were analyzed (aggregation period: February 12, 2021 to May 17, 2021). The database was created to store anonymized data of side effects related to veterinary drugs, which were reported according to the Act on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals and Medical Devices (Act No. 145 of August 10, 1960).

Of 66525 reports submitted to the U.S. Animal & Veterinary Adverse Events database⁸⁾ (made publicly available by openFDA in 2020), we analyzed 15860 reports with clear details related to off-label use of veterinary drugs to determine any deviations in use indicated in the package inserts.

Items Investigated

We retrieved information from the Japanese database regarding the drug name, compliance with the package insert, storage conditions, number of concomitant drugs, presence or absence of side effects history, and opinions of veterinarians and manufacturers.

Therapeutic Categories of the Drugs

Veterinary drugs with the same active ingredients as human drugs were classified into the corresponding therapeutic categories. In addition, those with a different intended use from the corresponding human drugs, and those that could not be properly classified, were assigned the therapeutic category name(s) described in the drug package insert.

RESULTS

According to the therapeutic category, the highest number of reports (577, 55.46%) was associated with antiparasitic drugs, and the top three categories of drugs were mentioned in 81.25% of all reports (Table 1). As shown in Table 2, 12 reports (0.83%) were related to humans: 5 reports of needlestick accidents (Nos. 6–10), 4 reports of drug exposure (Nos. 2, 3, 5, 11), 1 report of accidental ingestion of oral medicine by an owner (No. 4), 1 report of injury when opening a drug vial (No. 1), and 1 report of adverse effects of unknown origin (No. 12).

Table 1. Number of Veterinary Drug-Associated Side Effects Reported According to Therapeutic Category

Therapeutic category	Number of reported cases	Proportion (%)
Antiparasitic drugs	577	55.46
Antimicrobial drugs	207	14.39
Non-steroidal anti-inflammatory drugs (NSAIDs)	164	11.40
General anesthesia	46	3.20
Osteoarthritis symptom-improving agent*1	43	2.99
JAK inhibitor*1	41	2.85
Corticosteroids	35	2.43
Antiemetic drugs (neurokinin 1 receptor antagonists)	35	2.43
Interferon formulations*2	33	2.29
Ophthalmological drugs (NSAIDs)	32	2.23
Antineoplastic drugs	31	2.16
Immunosuppressants	29	2.02
ACE inhibitors	18	1.25
Injectable anesthesia for dogs and cats*1	15	1.04
Antiepileptic drugs	15	1.04
Corticosteroid synthesis inhibitor	14	0.97
Sedative hypnotic	13	0.90
Analgesics and painkillers	12	0.83
Otitis externa medicines	9	0.63
Canine anti-dog interleukin-31 monoclonal antibody preparation*1	9	0.63
Gastrointestinal disease medicines	8	0.56
Prostaglandin I2-derived preparation*2	7	0.49
Heart failure treatment	6	0.42
Analgesics/sedative antagonist*1	5	0.35
Biological preparations (vaccines)	3	0.21
Drugs for non-communicable canine osteoarthritis *1	3	0.21
Diabetes medicine	3	0.21
Thyroid disease medicine	3	0.21
Anti-inflammatory agent for the acute phase of canine Pancreatitis medicine*1	3	0.21
Angiotensin receptor blocker	3	0.21
Canine benign prostatic hyperplasia treatment*1	3	0.21
Other	13	0.90
Total	1438	100

*¹ Indicates the drug name as written in its package insert, and *² indicates a drug with a different use purpose as a human drug or veterinary drug.

Table 2. Reports of Human Incidents in the Veterinary Drug Database

No.	Report date	Product name	Therapeutic category	Non-proprietary name	Dosage form	Sex	Age	Administered by	Prefecture	Situation	Time to onset	Main Symptom(s)	Measures taken	Outcome
1	10/16/2020	Draxxin	Antimicrobial drug (macrolide)	Turraslomycin	Injection	—	—	Veterinarian	Hokkaido	A finger was injured by the metal piece at the mouth of the vial after removing the vial cap.	—	Fingertip injury	—	—
2	9/23/2020	Ivomec topical	Antiparasitic drug	Ivermectin	Injection	Male	—	Breeder	Gifu	The breeder was administering this drug to cattle when about 200–300 mL of the drug splashed onto both of his thighs over his pants. After about 5 min, the breeder took his pants off and washed the area with soap. Despite the absence of skin issues, asthma-like symptoms were noted.	50 min	Asthma-like symptoms	Washing with soap	Recovered
3	3/30/2020	Andres ointment	Non-steroidal anti-inflammatory drug	Methyl salicylate, l-menthol, dl-camphor	Topical drug	Male	31	Breeder	Aichi	After applying this drug to cattle with bare hands several times, the breeder experienced recurrence of alopecia areata.	—	Recurrence of alopecia areata	Treatment	Under treatment
4	3/6/2020	Remadile tablet 25	Non-steroidal anti-inflammatory drug	Carprofen	Tablet	Female		Owner	Chiba	The owner mistakenly ingested this drug and developed gastric discomfort.	—	Gastric discomfort	—	—
5	10/3/2019	Revolution plus	Antiparasitic drug	Selamectin, saloralenol	Topical drug	—	—	Owner	Shizuoka	The drug adhered to human fingers and caused skin redness	<1 h	Skin redness	Washing with running water	Recovered
6	7/5/2018	Ingelvac flex combo mix	Vaccine	Inactivating antigen of porcine circovirus type 2	Injection	Male	40	Breeder	Aichi	While vaccinating pigs, the person performing the injections had a needlestick accident, which later led to injection site swelling. It is unclear whether the agent was injected into the affected person.	<12 h	Injection site swelling	Treatment with antibiotics	Recovered
7	5/24/2018	Ingelvac flex combo mix	Vaccine	Inactivating antigen of porcine circovirus type 2	Injection	Male	—	Breeder	Yamanashi	While vaccinating pigs, the person performing the injections had a needlestick accident, which later led to injection-site swelling. It is unclear whether the agent was injected into the affected person.	<1 h	Injection site swelling, pain	Treatment with antibiotics	Recovered
8	5/9/2018	Micotil 300 injectable fluid	Antimicrobial agent (macrolide)	Tilmicosin	Injection	Male	58	Veterinarian	Oita	A used needle held by a veterinarian at the time of treating cattle stuck in the thigh of a breeder who was holding the animal in place. Pain and swelling of the affected area were observed later.	<10 min	Injection site swelling, pain	Treatment (cleaning and cooling affected site, drip infusion)	Recovered
9	4/12/2018	Micoral oral solution	Antimicrobial agent (macrolide)	Tilmicosin phosphate	Injection	Female	—	Breeder	Hokkaido	During treatment of cattle, misadministration of the drug to the breeder caused symptoms such as poor physical condition, difficulty in standing up, loss of appetite, abdominal pain, and loose stool.	2 d	Difficulty standing, loss of appetite, abdominal pain, soft stool	Treatment	Recovered
10	7/31/2015	Respisure one	Vaccine	Mycoplasma hyopneumoniae NL1042 strain Inactivated bacteria	Injection	Male	36	—	Kagoshima	While vaccinating pigs, a man accidentally stabbed himself in the finger with a needle when replacing a used needle, which caused pain, numbness, and swelling.	—	Pain, swelling, numbness	Treatment (disinfection at the hospital, taking antibiotics and herbal medicine)	Under treatment
11	11/8/2006	Pices	Other (antifungal agent)	Bronopol	Liquid for medicated bath	Male	65	—	Shizuoka	A man used this drug without wearing personal protective equipment (such as gloves, glasses, and a mask), which led to allergic reactions, eczema, and conjunctivitis in areas not covered with clothing. .	10 d	Allergic reaction, eczema, conjunctivitis	Treatment (vitamin C injection, ointment prescription at dermatology clinic)	Recovered
12	4/25/2003	Tilmicosin	Antimicrobial agent (macrolide)	Tilmicosin	Injection	Male	38	—	Tokyo	—	—	Chest and back pain, cyanosis, death	—	Death

Analysis of the storage conditions revealed that proper storage was recorded in 771 reports (53.62%), whereas in 647 (44.99%) reports the storage conditions were unknown, and in 20 (1.39%) reports, improper storage/management was evident (Fig. 1). Among the latter 20 reports, 18 cases of improper storage reflected room temperature storage of medicines that should have been refrigerated, and the remaining 2 cases involved the administration of drugs that were stored at proper temperatures but kept open for an unknown number of days before use (Table 3).

Fig. 1. Drug-Storage Conditions

Storage according to the conditions described in the package insert was classified as “appropriate storage.” Storage deviating from the recommended conditions or instances of inappropriate use were considered “inappropriate storage.” Instances where the storage conditions were unknown or not described were classified as “unknown storage.”

Table 3. List of Veterinary Drugs Used after Storage in Improper Conditions

No.	Product name	Therapeutic category	Non-proprietary name	Dosage form	Storage conditions indicated in the package insert	Actual storage conditions and notes	Number of reports
1	Cytopoint® 10	Canine anti-dog interleukin-31 monoclonal antibody preparation	Lokivetmab	Injection	2–8 °C	Room temperature	1
2	Convenia® Injection	Antimicrobial drug	Cefovecin	Injection	2–8 °C	Room temperature	2
3	Onsior® Injection	Non-steroidal anti-inflammatory drug	Robenacoxib	Injection	2–8 °C	Room temperature	14
4	Antisedan®	Analgesic/sedative antagonist	Medetomidine hydrochloride	Injection	Room temperature	Room temperature, use of drug for which the date of opening was unknown	2
5	Allermmune® HDM0.1	Canine atopic dermatitis-desensitization therapy	Recombinant Der f 2 - pullulan conjugate	Injection	2–8 °C	Room temperature	1

Of the 1308 reports containing information regarding clear compliance with the drug package insert, 840 reports (64.22%) mentioned that the medicine was used according to the intended dosing, administration, and indications described in the package insert (Fig. 2). Nevertheless, 468 reports (35.78%) mentioned uses that deviated from the package-insert instructions, of which 5 cases involved the use of a drug with the understanding that it would deviate from the package-insert instructions, and 20 cases involved the evaluation of an adverse event based on human drug information. Table 4 provides a detailed description of the 467 reports in which deviated drug use was apparent. The most common deviation was deviation from the indication (259 reports, 55.46%). The number of deviations reported to the FDA was different than that reported in Japan, although similarities in the types of deviations were observed (Table 5).

Fig. 2. Compliance with Drug Package Insert Information

Table 4. Deviations from the Method of Use Described in the Package Insert

Deviation from the method of use described in the package insert	Number of reports	Proportion (%)
Indication	259	55.46
Dosage method (other than the intended route of administration)	83	17.77
Animal species	43	9.21
Route of administration	30	6.42
Exceeding the maximum number of treatment days	13	2.78
Administration to an animal below the dosing standard age	12	2.57
Contraindication	11	2.36
Overdosing	11	2.36
Underdosing	3	0.64
Exceeding the maximum number of doses	2	0.43
Total	467	100

Note: Based on the results of compliance with the instructions in the package insert (Fig. 4), the deviations and corresponding numbers of reports are indicated for 467 out of 468 instances where the details of deviation were clear.

Table 5. Description of 15860 Cases of Off-Label Use of Veterinary Drugs Reported to the U.S. Food and Drug Administration (FDA)

Deviation from the method of use described in the package insert	Number of reports	Proportion (%)
Off-label treatment regimen	5080	32.03
Off-label indication	2915	18.38
Overdosed	2600	16.39
Underdosed	2016	12.71
Other off-label issues	1494	9.42
Off-label species	1243	7.84
Off-label route	352	2.41
Product expired	108	0.68
Off-label storage condition	22	0.14
Total	15860	100

Note: The information presented is based on data for animal-related adverse events submitted to the U.S. openFDA Animal & Veterinary Adverse Events during 2020.

Regarding the use of concomitant drugs, 727 (50.98%) of 1426 reports indicated the use of only the suspect drug, whereas 663 reports (46.50%) indicated concomitant drug administration (Fig. 3A). Among the concomitant drug cases, most were a combination of two drugs (327 reports) and two reports indicated the involvement of 10 concomitant drugs (Fig. 3B).

Fig. 3. Concomitant Drug Uses Other than the Suspected Drug

(A) Presence or absence of concomitant drugs use. (B) Number of concomitantly administrated drugs identified in 663 reports.

Regarding the presence or absence of side effect history, 682 (47.83%), 655 (45.93%), and 89 reports (6.24%) described unknown, absence, and presence of side effect history, respectively (Fig. 4A). Of the 89 “presence” reports, 35 indicated the occurrence of side effects to the same drug and same active ingredient that were administered previously, and 6 reports indicated side effects to a similar ingredient that was administered previously. These findings show that nearly half of all reports of adverse reactions after administering drugs with a history of side effects involved the same drug, a drug with the same active ingredient, or a similar active ingredient to a drug that had been administered previously (Fig. 4B).

Fig. 4. Presence or Absence of History of Drug-Related Side Effects

(A) Characterization of drug-related side effects. (B) Suspected drugs identified in 89 reports as having a history of side effects.

DISCUSSION

To the best of our knowledge, this study is the first to elucidate pharmaceutical issues related to drugs used in veterinary medicine in Japan based on reports of their side effects. Notably, some drugs with reported adverse reactions were found to be managed and/or administered in manners that deviated from the conditions described in the package insert. This indicated the fact that veterinary professionals may be struggling to treat companion animals owing to lack of drugs for appropriate treatment. The identified package-insert deviations (Tables 4, 5) were presumed to include carelessness-associated medical malpractice. On the other hand, from another perspective, the Japan Veterinary Medical Association allows the use of medicines deviating from the package insert instructions in the absence of other available medical treatment.⁹⁾ Hence, off-label drug use may be the result of the large unmet medical needs of approved veterinary medicines. The background factors that lead to adverse events are considered to be rooted in the underdevelopment of evidence-based veterinary medicine,³⁾ in addition to other problems related to veterinary medicine, such as the species differences,¹⁰⁾ lack of pharmacist job positions,¹¹⁾ and medical economic aspects, such as considering the balance between medical expenses and cost price under treatment not covered by health insurance.¹²⁾

Although the risk of adverse events in polypharmacy has been shown to be high in humans,¹³⁾ taking several drugs concomitantly, as demonstrated in this study, is also considered a risk factor in the field of veterinary medicine. Furthermore, the side effect that often occurred upon re-administering a drug to an ill animal with a previous adverse effect history, is also a risk factor. Thus, proper pharmaceutical management based on information regarding the affected animal may contribute to reducing the risk of adverse events. In general, students have limited opportunities to learn about animals during their pharmacy education, but pharmaceutical researchers and pharmacists are in a position to contribute to veterinary medicine. The provision of more detailed drug information and appropriate drug management could not only assist animal health care providers, but could also contribute to the promotion of the proper use of drugs and the enhancement of human health. However, studies based on pharmaceutical perspective in Japanese veterinary medicine have been limited to a few areas, such as investigations on adverse reactions to vaccines¹⁴⁾ and the handling of anticancer drugs.¹⁵⁾

Taken together, these findings suggest that there is room for improving the collection and utilization of drug information, research, and pharmaceutical care to avoid adverse events in veterinary medicine in Japan. Development of veterinary medicine pharmacology in response to the actual clinical situation in Japan, and increased opportunities for specialized education, are still warranted to optimize pharmacotherapy for ill companion animals.

Acknowledgments

We would like to express our sincere gratitude to Dr. Kenji Hoshi of the Division of Medical and Pharmaceutical Information Science, Tohoku Medical and Pharmaceutical University for all valuable insights. We would also like to express our sincere gratitude to Shiho Miyauchi of our group for collecting the data.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

This article contains supplementary materials.

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