Excipients of concern in the package inserts of human medicines prescribed in veterinary pharmacotherapy: frequency and implications for animal healthAbstract
The therapeutic arsenal for veterinary pharmacotherapy includes both medicines for exclusive veterinary use and human medicines prescribed off-label for animals. Unlike medicines for exclusive veterinary use, the package inserts of human medicines detail the qualitative composition of the excipients in these products. Some excipients may cause adverse reactions in specific animal populations, necessitating that healthcare professionals identify and avoid administering medicines containing these excipients to susceptible animals. In this study, we analyzed 120 package inserts for human medicines prescribed for animals and, identified 14 excipients of concern for this population: 10 in liquid products, 6 in semi-solid products, and 5 in solid products. The identified excipients include ethyl alcohol, benzyl alcohol, benzalkonium chloride, mannitol, sodium metabisulfite, sodium lauryl sulfate, propylene glycol, polyethylene glycol, polysorbate, and ethoxylated castor oil. Although off-label use of human medicines in veterinary practice is permitted, the study suggests that regulatory agencies and professional councils should raise awareness among veterinary prescribers and pharmacists regarding these excipients. This unprecedented study highlights the urgent need to address this issue, aiming to encourage research on excipient safety in animal populations and strengthen veterinary pharmacovigilance services.
Key words
Veterinary pharmacy; concerning excipients; package inserts; animal health
INTRODUCTION
Medicines are technically elaborated products, obtained from the mixture of one or more active pharmaceutical ingredients (APIs) and excipients, submitted to a manufacturing process in pharmaceutical laboratories or compounding pharmacies (Reker et al. 2019). In many cases, excipients account for the bulk or volume of APIs (Allen Jr & McPherson 2018, Klátyik et al. 2017). Until the 2000s, the importance of excipients was considered irrelevant, and these pharmaceutical ingredients were known as inactive (Baldrick 2000). The concept of “inactive” does not align with the chemical and biological activities and functionality of excipients; therefore, these ingredients should not be conceptualized as inactive (Klátyik et al. 2017, Baldrick 2000, Golightly et al. 1988, García-Arieta 2014).
Currently, the definition of excipient encompasses aspects related to its influence on the performance of medicines, as it can impact the absorption and bioavailability of the API. This is because excipients interfere with physiological processes in the gastrointestinal tract, modifying transit and gastric emptying times, altering intestinal permeability, and affecting the metabolism of the API. Excipients such as polyols (mannitol, sorbitol, xylitol, and polyethylene glycol 400) are osmotic agents that can reduce the absorption of the API by increasing the intraluminal fluid volume, diluting the API, and reducing its concentration, thereby compromising the efficacy of the treatment (Metry & Polli 2022, García-Arieta 2014). From a pharmacological perspective, certain excipients can promote physiological changes in the organism. Examples include lactose, aspartame, and sucrose, which can cause adverse reactions (ARs) in animal species with lactose intolerance, phenylalanine intolerance, and in cases of insulin resistance and diabetes (Sheskey et al. 2020). In addition, benzoic acid, sodium benzoate, and sodium metabisulfite can accumulate and cause ARs in animals with deficiencies in the glucuronidation metabolic pathway. Benzyl alcohol is rapidly oxidized by the enzyme alcohol dehydrogenase and converted to benzoic acid, which also characterizes it as a potential agent for causing ARs (Caloni et al. 2014, Court 2013, Sheskey et al. 2020). Finally, the excipient should also be conceptualized based on its quality parameters, the function it performs in formulations and manufacturing processes, and the existence of chemical reactivity of its molecules, which can induce degradation reactions in the product and trigger biological effects (Baldrick 2000, Golightly et al. 1988, Ramesh et al. 2019, Sheskey et al. 2020). Taking all these aspects into consideration, the concept of excipient was updated: an excipient is defined as any pharmaceutical ingredient, other than the API, which, after having its quality, safety, and toxicity evaluated, is included in pharmaceutical dosage forms to perform a specific function (Sheskey et al. 2020).
Although the market for veterinary pharmaceutical products is experiencing significant growth worldwide, veterinary pharmacotherapy still faces a major obstacle: the development of new APIs and medicines for exclusive use in all animal populations. This is due to the considerable physiological variability between species and the high costs associated with the research and manufacturing of medicines exclusively for this population, which would impact the profits of pharmaceutical laboratories and the availability of high-cost medicines (Rollin 2002, Tomanic et al. 2021, Nind & Mosedale 2022). For this reason, the off-label administration of medicines for human use in veterinary pharmacotherapy by cascade prescribing or historical dose adjustment allows, under certain circumstances, is useful for expanding the veterinary pharmacotherapeutic arsenal and providing rapid access to available market products for animals, bringing benefits to veterinary clinical practice (VMD 2013, CVMA 2021, Jaime et al. 2022, Nind & Mosedale 2022).
Cascade prescribing, or simply cascade, aims to increase the therapeutic arsenal available for veterinary pharmacotherapy to avoid unacceptable animal suffering when there is no alternative to pharmacological treatment for a specific pathology or target species. It consists of a decision tree or flowchart that allows the veterinarian to choose the medicine that is best suited for the treatment, even if the medicine is not authorized for the target species. In the cascade, the veterinarian must prescribe, whenever available on the market, a medicine for exclusive veterinary use that is authorized for the intended indication. In its absence, the prescriber may choose a veterinary medicine used in a manner different from that specified in the package insert or other legal documents, including use in another species to treat a different disease or with a different dosage regimen. When this option also does not exist, the prescriber may opt to prescribe a human medicine to meet the therapeutic needs of the animal. The final option in the cascade is the prescription of a compounded veterinary medicine, also known in the veterinary community as an extemporaneous preparation. The decision tree may vary depending on the species and whether they are intended or not for food production (Nind & Mosedale, 2022, Nogueira et al. 2024).
Regulatory agencies worldwide, responsible for approving product registrations, overseeing industrial production, regulating and supervising the compounding of medicines, and authorizing the marketing of medicines, permit the incorporation of three types of excipients in products intended for both human and exclusive veterinary: (i) excipients listed as safe due to their established use in the food and medicines industries, known as Generally Recognized as Safe (GRAS); (ii) excipients chemically derived from those listed as GRAS; and (iii) new excipients, usually polymer-based, required for the preparation of advanced therapeutic performance API delivery systems, such as micro and nanocarriers (Sheskey et al. 2020, Saluja & Sekhon 2013, Pifferi & Restani 2003, Villanova et al. 2010). However, even excipients listed as GRAS can trigger ARs in target populations, given the possibility of hypersensitivity, immunogenicity, absence of enzymes that impair the metabolism of these ingredients, intolerance, or treated or pre-existing health conditions in animals (Reker et al. 2019, Baldrick 2000, Klátyik et al. 2017). In these cases, these components are known as excipients of concern and should be evaluated together with APIs as possible causes for ARs (Baldrick 2000, Abrantes et al. 2016, Pifferi & Restani 2003, Napke 2004). A detailed review on concerning excipients for the animal population is presented in the study by Thomazini et al. (2023): the authors warn that among 135 studies of ARs or cases of poisoning in animals due to these ingredients, only 24 adequately evaluated the inclusion of these substances as excipients in medicines.
The package insert is a valuable source of information for prescribers and other health professionals involved with veterinary pharmacotherapy to investigate the presence of excipients of concern (Strauss & Greeff 2015). According to Golightly et al. (1988), listing in package inserts all the excipients that compose pharmaceutical formulations, in addition with good manufacturing practices, is an action that aids prescribers and pharmacists to identify the presence of excipients of concern and predict the possibility of occurrence of ARs potentially caused by them, favoring pharmacovigilance actions, and avoiding inadvertent administration to animals, reducing the risks of health damage. It should be noted that, according to regulatory agencies worldwide, only the qualitative composition of excipients should be reported in the package inserts, without the obligation to disclose the quantity. In addition, it should be considered that excipients are included in the formulations according to the maximum proportions recommended in the Handbook of Pharmaceutical Excipients or according to data from the technical and scientific literature consulted by pharmaceutical laboratories (Reker et al. 2019, Sheskey et al. 2020).
In this context, the objective of this study was to determine the frequency of the presence of excipients of concern in the package inserts of human medicines prescribed for animals and to highlight the potential for the occurrence of ARs. According to Napke (2004), in addition to pharmacovigilance actions that aim to study ARs derived from APIs, toxicity data and ARs caused by excipients in products for human and veterinary use should be compiled and reported. The study also aimed to encourage research in the area of veterinary pharmacovigilance and seeks to provide support for the implementation of rules by regulatory agencies regarding the inclusion of lists of excipients in the package inserts of medicines intended exclusively for veterinary use, following the models established worldwide for medicines for human use.
MATERIALS AND METHODS
This is an exploratory documentary study using qualitative and quantitative approaches, in which package inserts of medicines for human use that are also prescribed for animals were evaluated to identify and assess the frequency of the excipients of concern included in the formulations. Descriptive statistics were used for data analysis. Only package inserts of reference medicines classified under group A (monodrug) according to the Agência Nacional de Vigilância Sanitária (ANVISA) were considered for this study. Moreover, included package inserts had to be found in the packaging of market medicines available in liquid, solid, and semisolid dosage forms for both internal and external use, with both local and systemic actions, and administered orally, parenterally (intravenously and intramuscularly), topically, and ophthalmically. In cases in which medicines showed more than one presentation of the API dose, the list of excipients included was from the presentation with the smallest commercially available dosage. The consultation of APIs to define the medicines was conducted using the Saunders Handbook of Veterinary Drugs (Papich 2016) by a veterinary prescriber. A total of 120 package inserts for human medicines were selected from the List of Reference Medicines for 2024, which is available for free public consultation on the ANVISA website (https://www.gov.br/anvisa/pt-br/setorregulado/regularizacao/medicamentos/medicamentos-de-referencia). The excipients of concern for the animal population whose presence was investigated were those included in the list compiled by Thomazini et al. (2023): benzoic acid, benzyl alcohol, ethyl alcohol, bentonite, sodium benzoate, sodium carboxymethylcellulose, benzalkonium chloride, monosodium glutamate, lactose, sodium lauryl sulfate, mannitol, sodium metabisulfite, mineral oil, polyethoxylated castor oil, propylene glycol, polyethylene glycol, polysorbate, and xylitol. There was no delimitation of API therapeutic classes or animal species. Package inserts with combinations of APIs, hormones, vitamins and supplements, vaccines, and APIs of a biological or biotechnological nature were not included in the study.
RESULTS AND DISCUSSION
The rational use of medicines in veterinary pharmacotherapy ensures that the treatment achieves its intended efficacy within the expected duration; minimizes potential ARs, thereby enhancing patient safety; reduces the risk of residues of APIs in food, thereby contributing to human health preservation; lowers treatment costs; and in the case of antimicrobials, helps in reducing the emergence of resistant microbial strains (Beyene & Tesega 2014, Beyene et al. 2015). According to Rollin (2002), the off-label use of medicines for humans in the animal population is valid if it involves the consent and commitment of the owner or caretaker to the treatment, the adhesion and comfort of the animal, as well as the pharmacotherapeutic monitoring by the veterinarian, who must adhere to principles of continuous education about pharmaceutical dosage forms and obtain updated and comprehensive information about pharmacology. There are many reports in the literature about the occurrence of ARs in animals related to APIs contained in off-label human-use medicines (Gehring 2001, Dowling 2002, Woodward 2005, Naidoo & Sykes 2006, Mouiche et al. 2019, Mount et al. 2021). On the other hand, as already mentioned, occurrences of ARs due to excipients are scarcely researched and reported (Thomazini et al. 2023, Davidson 2017, Young et al. 2017). In a survey by the Bureau of Veterinary Drugs (BVD) of Canada, conducted from 1889 to 1991, 69 ARs were reported for APIs used as indicated in package inserts and for off-label use, of which only two related ARs to excipients (BVD 1992). However, it is important to highlight that the information about the excipients of concern in medicines is not easily accessible to healthcare professionals, except in package inserts.
In this study, 120 package inserts of medicines for human use prescribed for animals in an off-label manner were analyzed. All package inserts contained the list of excipients included in the formulations, in accordance with the ANVISA rules (Brasil 2022a). Of the total package inserts analyzed, 48 were for solid pharmaceutical dosage forms, 48 for liquid dosage forms, and 24 for semisolid dosage forms. Table 1 shows the list of excipients included in formulations according to medicines.
Excipients identified in medicine package inserts grouped according to pharmaceutical dosage forms and routes of administration, and excipients of concern for animals.
We identified fourteen (14) excipients of concern for which there are ARs or cases of toxicity previously reported in animals exposed to these ingredients by the same routes. Most of the excipients (10) were included in liquid dosage forms, which is consistent with the composition of these products. When compared to solid dosage forms, aqueous liquids dosage forms are more unstable from a microbiological, chemical, and physical point of view, given the presence of free water and the degradation kinetics of APIs, which is higher in aqueous media (Allen Jr & McPherson 2018). Reker et al. (2019) employed computational analysis of data available in the literature and identified a high incidence of excipients in liquid medicines with the potential to cause ARs. This fact is justified by the chemical reactivity of the excipients used as stabilizers, a necessary condition for them to exert their actions in the formulations (Allen Jr & McPherson 2018, Klátyik et al. 2017, Baldrick 2000, Pifferi & Restani 2003, Abrantes et al. 2016). In semisolid medicines, six (6) excipients of concern were identified, while in solid medicines, five (5) were identified.
In the package inserts of liquid medicines (solutions and suspensions) intended for oral, ophthalmic, and parenteral administration, the presence of sodium metabisulfite and sodium benzoate was identified; sodium metabisulfite was also present in semisolid formulations (creams and gels). On the other hand, benzalkonium chloride and benzyl alcohol were observed in the package inserts of ophthalmic solutions and suspensions; and benzyl alcohol was also found in cream package inserts. Polysorbates, ethoxylated castor oil, and ethyl alcohol were observed in the package inserts of intravenous solutions. Polysorbates were also identified in creams and in solid oral medicines, namely capsules and tablets. Sodium lauryl sulfate was found in liquids and solids. Propylene glycol and polyethylene glycol were present in the package inserts of oral and topical solutions, both in liquid and semisolid dosage forms. Finally, mannitol was found in package inserts of oral solid dosage forms, such as solutions, capsules, and tablets. Figure 1 a, b, c and d, shows the frequencies at which the excipients of concern were observed in the medicines package inserts.
Frequency of excipients of concern in the total number of package inserts (a); in package inserts of liquid medicines (b); semisolid medicines (c); and solid medicines (d).
Benzyl alcohol, benzoic acid, and sodium benzoate are excipients of concern often added in liquid formulations as preservatives. In most animal species, benzyl alcohol is metabolized to benzoic acid, which is excreted as glucuronide or conjugated with glycine. However, cats are unable to metabolize these ingredients via the glucuronidation route due to a deficiency of the enzyme glucuronyl transferase. On the other hand, the conjugation with glycine is very slow. For this reason, these excipients can accumulate in the organism and cause toxicity in cats. ARs to these excipients can occur in animals after exposure to a single dose of medicines containing them, even when included under the conditions deemed safe for these ingredients (GRAS) (Sheskey et al. 2020, Cullison et al. 1983, Court 2013). Although more common in cats, ARs to these excipients have been observed in dogs and birds (Thomazini et al. 2023).
Benzalkonium chloride (BC) is a quaternary ammonium excipient commonly used as a preservative in eye drops, including products intended for chronic use in the treatment of glaucoma. The literature discusses the pro-apoptotic and pro-inflammatory actions of BC, and its administration in eye drops can significantly damage the tear film, resulting in epithelial dysfunction of the ocular surface. This can cause conjunctival hyperemia, ocular secretion, and discomfort (Sheskey et al. 2020, Burstein 1980). Faria et al. (2019) confirmed the occurrence of corneal lesions in rabbits that received BC at a concentration of 0.1% for 30 days. Additionally, corneal epithelial desquamation, erosions, ulceration, and corneal neovascularization have been observed in cats, rabbits, guinea pigs, and dogs at excipient concentrations ranging from 0.001% to 0.01% (Caloni et al. 2014, Yang et al. 2017).
Sulfites, such as sodium metabisulfite, are commonly used as antioxidant agents in liquid and semisolid dosage forms. Sulfites are metabolized by oxidation to sulfates, which are excreted in the urine, releasing sulfurous acid, an irritant and toxic compound. Animals with a history of hypersensitivity reactions, respiratory problems, and bronchospasm are particularly sensitive to the presence of sulfites in liquid formulations for oral, intravenous, pulmonary, and topical use (Sheskey et al. 2020, Lavergne et al. 2016). Adverse reactions to sulfites have been reported in dogs, cats, and birds (Thomazini et al. 2023). In package inserts and labels of medicines intended for human use, to treat diseases related to the upper airways and cases of allergy, the term “sulfite free” is commonly present.
Exposure to ethyl alcohol, whether via oral ingestion or skin contact, can have toxic effects on dogs and cats, which are dose-dependent. Ethyl alcohol can be included in liquid formulations as a preservative, co-solvent, or the unique vehicle in elixir, thus attention should be given when dispensing oral, parenteral, and topical medicines that contain it (Sheskey et al. 2020, Post 2009).
The different types of polysorbates and polyethoxylated castor oil are excipients used as solubilizers in formulations containing poorly soluble APIs and in emulsified systems, such as emulsifiers. Some studies that report the occurrence of toxicity in different animals due to the presence of these ingredients in liquid formulations, mainly for parenteral and topical use (Sheskey et al. 2020, Bates 2017, Pouliot et al. 2022). ARs in cats, dogs, cattle, rabbits, broiler chicken, and fishes have been reported for these excipients (Thomazini et al. 2023). Toman et al. (1992) observed the occurrence of ARs caused by polysorbate 80 in cattle following the administration of vaccines. Susceptible animals that received these vaccines exhibited clinical signs of classic anaphylactic reactions, including restlessness, salivation, pruritus, edema and cyanosis of the uterus and vulva, and eyelid edema. The results indicated that the severity of reactions could be classified as weak, moderate, or strong, depending on the concentration of polysorbate 80 and the animal receiving the vaccine containing the excipient.
Propylene glycol and polyethylene glycol were found in the package inserts of oral and topical solutions and suspensions. Propylene glycol is widely used in parenteral, oral, otic, pulmonary, and topical medicines, and can be included as a co-solvent or as a unique vehicle in formulations. High levels of propylene glycol in the blood can trigger oxidative damage and shorten the lifespan of red blood cells. Small doses in cats can stimulate the formation of Heinz bodies in red blood cells and trigger anemia. Chronic inflammatory changes in the middle ear cavity and tympanic membrane can lead to epidermal hyperplasia, potential epidermal invasion, keratinization, and cholesteatoma formation. Moreover, degeneration of goblet cells in the tracheal epithelium has also been documented. ARs for propylene glycol are documented for cattle, dogs, cats, guinea pigs, horses, birds, calves, sheep, rabbits, chinchillas, and llamas. It is recommended that medicines containing propylene glycol be administered with caution to these populations (Papich 2016, Ruble et al. 2006, Claus et al. 2011). There have been reports of systemic toxicity to polyethylene glycol in rabbits, horses, dogs, and monkeys after exposure to oral, parenteral, and topical medicines. After absorption, polyethylene glycol is metabolized to acidic alcohols and diacids, which are responsible for toxicity to kidney and skin cells. In animals with extensive burns, open wounds, and renal insufficiency, medicines with these excipients must be used with caution (Sheskey et al. 2020, Papich 2016, Herold et al. 1982).
Finally, mannitol was found in package inserts of oral solutions (liquid and solid) and there are reports that it can cause ARs in dogs. Mannitol shows a tendency to lose hydrogen ions in aqueous solutions, making them acidic. It can induce diuresis and cause electrolyte disturbances, dehydration, hypovolemia, and cardiovascular collapse, and its use is contraindicated in hypovolemic patients. Moreover, when ingested orally in large doses, it can cause osmotic diarrhea and severe hypovolemia. If inhaled, mannitol can cause bronchospasm and hemoptysis (Sheskey et al. 2020, Caloni et al. 2014).
For Karriker & Wiebe (2006), the inclusion of excipients of concern in medicines for humans used in small animals and exotic species can cause toxic effects and ARs, and it is necessary to evaluate the species-specific susceptibility to the possible effects of these ingredients since the metabolism and excretion of these components can vary between different species. Considering that these ingredients are not chemically inert and can cause physiological changes, their high prevalence in formulations, and their use in different quantities and dosage forms, prescribers and pharmacists should recognize that these components have the potential to trigger ARs in animals, increasing clinical awareness regarding the potential harm they can cause to health (Ionova & Wilson 2020). Therefore, veterinarians and pharmacists should have easy and rapid access to the information contained in package inserts about the presence of excipients of concern.
Given the significant nature of the topic regarding rational medicine use and human health, ANVISA revised the regulation governing warning statements that must be present on labels and package inserts of medicines containing APIs and excipients considered of concern to humans (Brazil 2022b). According to the standard, warning phrases are provided for the specific conditions of use of benzyl alcohol, lactose, sucrose, sodium benzoate, sulfites, ethyl alcohol, and mannitol. Examples of these alerts include: “Attention: this medication contains benzyl alcohol”; “Attention: contains alcohol (ethanol)”; “Attention: contains ___% of alcohol (ethanol)”; “Attention: this medication contains ___ (insert the name of the sulfite; for example, sodium metabisulfite), which can cause severe allergic reactions, especially in asthmatic patients”; “Attention: contains ___ mg of ___ (type of sugar)/pharmaceutical unit or unit of measure”; “Attention: should be used with caution by patients with diabetes”; “Attention: contains ___ (type of sugar)”; and “Attention: contains ___ (mannitol, maltitol, or sorbitol) in an amount that may cause a laxative effect”; among others.
If a pharmaceutical laboratory considers including an excipient in a medicine, it must be prepared to demonstrate the safety of the target population to the presence of this ingredient in the formulation, in its usual concentration, based on the toxicity and safety data available about the excipient (Golightly et al. 1988, Pifferi & Restani 2003, Saluja & Sekhon 2013, Osterberg & See 2003). Veterinarians, pharmacists, and other healthcare professionals involved in veterinary pharmacotherapy should thoroughly review the packaging, labels, and package inserts of medicines, paying close attention to this information. This practice aims to minimize risks and facilitate the substitution of medicines containing excipients of concern with alternatives that are free from these ingredients or to guide the selection of medicines that do not include them. One viable option is to prescribe compounded veterinary medicines, as an advantage of these products is the individualization of formulations, including the selection of excipients used (Davidson 2017).
CONCLUSIONS
The list of excipients extracted from the package inserts of human medicines analyzed showed the presence of excipients of concern for animals. These excipients have the potential to cause adverse reactions in susceptible populations, even when included in formulations under correct conditions of use. Identifying the presence of these excipients in the package inserts of human medicines prescribed for animals contributes to the rational use of medicines in veterinary pharmacotherapy. Although cascade prescribing of human medicines for animals is permitted, veterinarians and pharmacists must be capable of identifying these ingredients in the package inserts before administration, thereby contributing to animal safety. The findings of the present study highlight a problem neglected by professionals and researchers and should be taken into consideration by regulatory agencies and professional councils for the provision of continuing education for those involved in veterinary pharmacotherapy.
The main limitations of this study were the exclusion of medicines package inserts with combinations of APIs, hormones, vitamins, vaccines, and medicines of a biological or biotechnological nature from the study. For future projects, it is recommended to broaden this scope in order to enhance understanding of the issue and support solutions and educational actions for healthcare professionals involved in veterinary pharmacotherapy.
ACKNOWLEDGMENTS
This study was supported by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES, Brazil) and by the Fundação de Amparo à Pesquisa e Inovação do Espírito Santo (FAPES, Brazil) by funding Notice nº 18/2020; TO 0137/2021.
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