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Background: Evaluate the clinical safety of robenacoxib in cats with chronic musculoskeletal disease (CMSD)., Animals: Four hundred forty-nine client-owned cats with CMSD., Methods: Pooled analysis of safety variables from 4 prospective randomized blinded clinical trials of robenacoxib (n = 222) versus placebo (n = 227), administered orally once daily for 4 to 12 weeks. Safety was evaluated from reported adverse events (AEs) and abnormalities detected on hematology and serum and urine chemistry analyses., Results: The number of cats with at least 1 AE was not significantly different (P = .15) with robenacoxib (n = 106, 47.8%) compared to placebo (n = 93, 41.0%). The relative risk of at least 1 AE (incidence robenacoxib/placebo) was 1.15 (95% confidence interval 0.93-1.43). There was no significant difference between groups in the number of clinical signs (range, 0-9) per cat (P = .23). Serum creatinine concentrations were higher during robenacoxib administration compared to placebo (+4.36 μmol/L, 95% confidence interval 0.21-8.50), but no related adverse clinical effects were detected. In the subgroup of 126 cats with evidence of chronic kidney disease, the relative risk of at least 1 AE (robenacoxib/placebo) was 1.09 (95% confidence interval 0.78-1.52, P = .61)., Conclusions and Clinical Importance: Robenacoxib was not associated with increased risk of AEs compared to placebo when administered for 4 to 12 weeks to cats with CMSD. The generalizability of the results to general practice is limited by the fact that cases with severe and uncontrolled concomitant diseases were not included., (© 2021 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Background: Studies show that the novel isoxazoline, lotilaner (Credelio™ CAT; Elanco Animal Health), which is administered orally to cats, provides rapid and sustained flea kill for least 1 month following administration with a wide safety margin. A clinical trial was undertaken to confirm its efficacy, impact on flea allergy dermatitis (FAD) and safety under field conditions., Methods: A total of 343 cats were enrolled in the study at 11 veterinary clinics in the USA. Upon inclusion, cat households were randomized at a ratio of 2:1 to receive lotilaner tablets at the recommended dose (minimum 6 mg/kg) or a topical formulation containing fipronil + S-methoprene (Frontline® Plus for cats; Boehringer Ingelheim), administered per label. Owners were dispensed treatments for administration on days 0, 30 and 60; all household cats were administered the same treatment. Flea counts were made on primary cats (1 cat per household) on days 0 (pre-treatment), 30, 60 and 90. Flea allergy dermatitis was assessed on days 30, 60 and 90 for all cats with signs of FAD on day 0. Lotilaner-treated cats were also assessed for their acceptance of oral tablet administration by the pet owner, and safety was assessed for all cats in both groups., Results: Lotilaner efficacy was 98.3, 99.9 and 99.9% on days 30, 60 and 90, respectively, while the efficacy of fipronil + S-methoprene was 61.6, 75.4 and 84.7%, respectively (P < 0.0001, within both groups and all days). Flea counts were significantly lower in the lotilaner group than in the fipronil + S-methoprene group (P < 0.0001) on each assessment day. On day 90, 98.3% of lotilaner-treated cats and 28.8% of fipronil + S-methoprene-treated cats were free of fleas. Owners successfully administered 99.5% of tablets to their cats. Total FAD score was reduced significantly following treatment in both groups by day 30 (lotilaner: P < 0.0001; fipronil + S-methoprene: P = 0.0041) and continued to decrease following multiple treatments. Total FAD scores were also significantly lower in the lotilaner group than in the fipronil + S-methoprene group on day 90 (P = 0.0006 for FAD total score). Pruritus scores were significantly lower in the lotilaner group on all assessment days., Conclusion: A single lotilaner treatment, administered by the pet owner, was > 98% efficacious in reducing flea counts within 30 days. Three consecutive monthly lotilaner treatments resulted in nearly 100% reduction in flea infestation. In the evaluations of flea counts, number of cats free from fleas and pruritus FAD score, lotilaner was shown to be superior to fipronil + S-methoprene at all time points. Lotilaner was more efficacious than fipronil + S-methoprene and was associated with greater reduction in FAD signs. Lotilaner flavored tablets were well accepted by cats. Adverse reactions were mild and infrequent, confirming the safety of lotilaner tablets in client-owned cats.

Background: Robenacoxib (Onsior™) is a non-steroidal anti-inflammatory drug developed for canine and feline use for the control of pain and inflammation. It is available as both tablets and solution for injection. The objective of this study was to evaluate the safety of the interchangeable use of commercially available robenacoxib formulations when administered to cats orally using 6 mg tablets and subcutaneously using a solution for injection containing 20 mg/mL. Thirty-four naïve healthy 4-month old cats were enrolled in this 37-day study and were randomized to four groups (three robenacoxib and one control). One robenacoxib group received the maximum recommended dose (MRD) rate of each formulation, while the other two received two and three times this dose rate. The cats underwent three 10-day treatment cycles comprised of seven days of once daily oral administration followed by three days of subcutaneous administration. The third cycle was followed by an additional seven days of oral treatment. The control group received oral empty gelatin capsules or subcutaneous saline injections. Assessment of safety was based on general health observations, clinical observations, physical, ophthalmic, electrocardiographic and neurological examinations, clinical pathology evaluations, food consumption, body weight, and macroscopic and microscopic examinations. Blood samples were collected for toxicokinetic evaluation., Results: Blood concentrations of robenacoxib confirmed systemic exposure of all treated cats. All cats were in good health through study termination and there were no serious adverse events during the study. There were no changes in body weight, food consumption, ophthalmic, physical or neurological examinations during the study. Treatment-related abnormalities were of low occurrence at all doses and included injection site changes (transient edema with minimal or mild, subacute/chronic inflammation histologically) and prolongation of the QT interval. These findings were consistent with previously observed findings in studies with robenacoxib administered separately orally or subcutaneously in cats. Thus, there were no adverse effects that could be attributed specifically to the interchangeable use of oral and injectable robenacoxib., Conclusions: This 37-day laboratory study supports the safety of interchanging robenacoxib injection at a daily dose of 2 mg/kg with robenacoxib tablets at a daily dose of 1 mg/kg, or vice versa.

Background: Heart disease is an important cause of morbidity and mortality in cats, but there is limited evidence of the benefit of any medication., Hypothesis: The angiotensin-converting enzyme inhibitor benazepril would delay the time to treatment failure in cats with heart disease of various etiologies., Animals: One hundred fifty-one client-owned cats., Methods: Cats with heart disease, confirmed by echocardiography, with or without clinical signs of congestive heart failure, were recruited between 2002 and 2005 and randomized to benazepril or placebo in a prospective, multicenter, parallel-group, blinded clinical trial. Benazepril (0.5-1.0 mg/kg) or placebo was administered PO once daily for up to 2 years. The primary endpoint was treatment failure. Analyses were conducted separately for all-cause treatment failure (main analysis) and heart disease-related treatment failure (supportive analysis)., Results: No benefit of benazepril versus placebo was detected for time to all-cause treatment failure (P = .42) or time to treatment failure related to heart disease (P = .21). Hazard ratios (95% confidence interval [CI]) from multivariate analysis for benazepril compared with placebo were 1.00 (0.57-1.74) for all-cause failure, and 0.99 (0.50-1.94) for forward selection and 0.93 (0.48-1.81) for bidirectional selection models for heart disease-related failure. There were no significant differences between groups over time after administration of the test articles in left atrium diameter, left ventricle wall thickness, quality of life scores, adverse events, or plasma biochemistry or hematology variables., Conclusions and Clinical Relevance: Benazepril was tolerated well in cats with heart disease, but no evidence of benefit was detected., (© 2019 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.)

Background: The purpose of this study was to determine and compare the voluntary acceptance of two oral liquid formulations of ciclosporin, investigational Atopica® oral solution (Elanco Animal Health) and Cyclavance® Oral Solution (Virbac), when given orally via syringe or offered freely after mixing with food to dogs.Twenty-five adult mixed breed dogs were selected for this two-phase study. In Phase 1, 12 (Group I) and 13 (Group II) dogs received Atopica® oral solution and Cyclavance® Oral Solution, respectively, daily for 7 days via an oral syringe. After a 3-day washout period, the dosing was switched for a further 7 days. For Phase 2, dosing was by acceptance from freely offered test article mixed in a small amount of food, approximately 6 h after the routine morning feeding. During the first part of this phase, normal daily ration of food offered in the morning was continuously left in the cage. Group I was offered Atopica® oral solution and Group II was offered Cyclavance® Oral Solution mixed with ~ 25 g of food for 3 days. After another 2-day washout period, the test articles were switched for another 3 days but the animals received food for only 1 h in the morning. Five hours after the food was removed, the test articles with food were offered in the same manner as in the first part of Phase 2. Animals were also monitored for adverse events (AEs)., Results: During Phase I, voluntary acceptance rates of 100 and 98.9% were noted for Atopica® oral solution and Cyclavance® Oral Solution, respectively. The corresponding immediate prehension rates during Phase 2 (Period 1) were 61.1 and 56.4%, respectively. During Phase 2 (Period 2), the immediate prehension rates were 69.2, 69.4 and 92.0% for Atopica® oral solution, Cyclavance® Oral Solution and the positive control (DYNE®; High Calorie Liquid Dietary Supplement), respectively. Two adverse events of diarrhea and vomiting, with a probable relationship to the test articles, were reported., Conclusion: There was no significant difference in acceptance of the two oral ciclosporin solutions, the investigational Atopica® oral solution (Elanco) and Cyclavance® (Virbac) for dogs., Competing Interests: Not applicableNot applicableSK, WS and KD are employees of Elanco Animal Health and are therefore eligible for stock and stock options. LC is an employee of Stillmeadow Inc.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Background: From three days following host attachment, the Australian paralysis tick, Ixodes holocyclus, secretes a neurotoxin that annually causes paralysis in approximately 10,000 domestic pets. Lotilaner, a novel isoxazoline formulated in a chewable flavoured tablet (Credelio TM ), produces rapid onset of acaricidal activity in dogs, with an efficacy duration of at least one month. Two studies were performed to determine the efficacy of lotilaner against I. holocyclus infestations over 3 months., Methods: Both studies included 16 dogs, ranked according to I. holocyclus counts on Day -5 (from infestations on Day -8) and blocked into pairs. One dog in each pair was randomized to be a sham-treated control, the other to receive lotilaner at a minimum dose rate of 20 mg/kg on Day 0. Dogs were dosed in a fed state. Infestations were performed in both studies on Days -8 (to determine the tick carrying capacity of each dog) -1, 28, 56, 70, 77 and 84, and additionally in Study 1 on Day 91, in Study 2 on Days 14 and 42. In Study 1, ticks were counted and assessed as alive or dead at 24, 48 and 72 h post-initial infestation and post-subsequent re-infestations. In study 2, ticks were counted at 24, 48 and 72 h post-dosing or post-re-infestation. Efficacy was determined by the percent reduction in live attached tick counts in the lotilaner group compared to control., Results: Within 48 h post-treatment in Study 1 and within 72 h post-treatment in Study 2 all lotilaner-group dogs were free of live ticks. By 72 h post-infestation, efficacy in Study 1 remained at 100% through Day 87, except on Day 31 when a single tick was found on one dog, and through Day 59 in Study 2. Efficacy exceeded 95% through the final assessment in each study (Days 94 and 87 in Studies 1 and 2, respectively)., Conclusion: These results demonstrate that lotilaner quickly kills existing I. holocyclus infestations. By providing 95.3-100.0% protection through at least 87 days post-treatment, lotilaner can be a valuable tool in reducing the risk of tick paralysis in dogs.

Background: Throughout Japan, Korea and China, Haemaphysalis longicornis ticks are vectors of Babesia gibsoni, which causes severe and progressive anemia in dogs. This study evaluated the efficacy of a single administration of lotilaner flavored chewable tablets (Credelio TM ) against experimental canine H. longicornis infestations., Methods: Twenty-two healthy Beagles were ranked in descending order of counts of H. longicornis completed 48 h after challenge on Day -7. The 16 dogs with the highest live tick counts were blocked into pairs and within pairs randomized to either lotilaner-treatment at a minimum dose rate of 20 mg/kg or sham-treated controls. Treatment was administered within 30 ± 5 min following feeding on Day 0. Infestations with 50 unfed adult H. longicornis were completed on Days -2, 7, 14, 21, 28 and 35. Elizabethan collars were placed for 48 (± 2) h after each infestation and a T-shirt was placed on each dog to facilitate attachment. Ticks were counted in situ 12 and 24 h post-treatment and counted and removed after an additional 24 h (48 h after treatment) and 48 h after each post-treatment infestation. Dogs were sedated for tick challenges and counts. Live attached ticks on each dog were counted for efficacy assessments. Lotilaner was considered effective if the average tick attachment rate in the control group was at least 20%, if there was a statistically significant difference (P < 0.05) in mean tick counts between treated and control groups, and if the lotilaner-treated group had a calculated efficacy of at least 90%., Results: Average control group retention of the H. longicornis challenge exceeded 20% at each assessment. Lotilaner started killing H. longicornis ticks quickly, achieving 57.4% efficacy within 12 h. At 48 h post-treatment, and following each subsequent infestation, between-group differences in mean H. longicornis counts were significant (P < 0.0001). From 48 h post-treatment, through the final assessment on Day 37, lotilaner efficacy remained greater than 95%, including on Day 37 when efficacy was 98.4%., Conclusion: Lotilaner, administered to dogs orally at a minimum dose rate of 20 mg/kg is well tolerated, provides rapid reduction of existing H. longicornis tick infestations, and provides sustained residual protection for at least 35 days.

Background: Lotilaner is a new isoxazoline developed as an oral ectoparasiticide for cats and dogs. Its safety, rapid killing onset of action and sustained speed of fleas and ticks kill for a minimum of one month after administration, were demonstrated in a number of laboratory studies in cats. This study was performed to demonstrate the efficacy and safety of lotilaner flavored chewable tablets for cats (Credelio™, Elanco) in controlling fleas under field conditions in European countries., Methods: Seventeen veterinary practices in France and Spain, located in high flea prevalence regions, participated in the study. Households with a maximum of three cats and two dogs were randomized 2:1 to a lotilaner (minimum dose rate 6 mg/kg) or a topical fipronil/(S)-methoprene combination (Frontline Combo® Spot-on Cats, Merial) group (administered according to label). In each household, efficacy against fleas and flea allergy dermatitis (FAD) signs were assessed in one primary cat (bearing a minimum of five fleas on Day 0) while safety was evaluated in all cats. There were 121 households included in the lotilaner and 61 in the fipronil/(S)-methoprene groups, respectively. Treatments were administered by the cats' owners on Day 0. Flea counts and FAD assessments were made on Days 0, 14, and 28. Efficacy calculations were based on geometric mean percent reductions of live flea counts versus baseline pre-treatment counts., Results: Lotilaner efficacy was 97.2 and 98.1% on Days 14 and 28, respectively. Corresponding efficacy for fipronil/(S)-methoprene was 48.3 and 46.4%. Lotilaner was superior to fipronil/(S)-methoprene at all post-Day 0 assessments and over the whole study period (P < 0.0001). At every post-administration evaluation, at least 81% of lotilaner-treated cats were flea-free as opposed to 25% in the fipronil/(S)-methoprene group. Lotilaner improved or eliminated clinical signs of FAD, including pruritus. Both products were well tolerated., Conclusions: Under field conditions in Europe, lotilaner flavored chewable tablets for cats displayed an efficacy against fleas higher than 97%; clinical signs of FAD were improved or eliminated. Lotilaner tablets were safe and provided superior flea control to fipronil/(S)-methoprene.

Background: Credelio TM (lotilaner) is an oral ectoparasiticide from the isoxazoline class developed for the treatment of flea and tick infestations in cats. It is formulated as a pure S-enantiomer in flavoured chewable tablets. The pharmacokinetics of lotilaner were investigated after intravenous or oral administration and under fed or fasted conditions in cats. Twenty-six adult cats were enrolled in a pharmacokinetic study evaluating either intravenous or oral administration of lotilaner. Following the oral administration at a dosage of 6 mg/kg, under fed or fasted conditions, or intravenous administration of 3 mg/kg, blood samples were collected up to 35 days after treatment. Lotilaner blood concentrations were measured using a validated liquid chromatography/tandem mass spectrometry method. Pharmacokinetic parameters were calculated by non-compartmental analysis. In addition, in vivo enantiomer stability of lotilaner was evaluated in a separate bioanalytical study., Results: Following oral administration in fed cats, lotilaner was readily absorbed and peak blood concentrations reached within four hours. The terminal half-life was 33.6 days. Food enhanced the absorption, providing close to 100% oral bioavailability and reduced the inter-individual variability. Following intravenous administration, lotilaner had a low clearance of 0.13 l/kg/day, large volumes of distribution V z and V ss of 5.34 and 5.37 l/kg, respectively and a terminal half-life of 28.7 days. In addition, there was no in vivo racemization of lotilaner., Conclusions: The pharmacokinetic properties of lotilaner administered orally as a flavoured chewable tablet (Credelio TM ) were studied in detail. With a T max of 4 h and a terminal half-life of 33.6 days under fed conditions, lotilaner provides a rapid onset of flea and tick killing activity with consistent and sustained efficacy for at least one month in cats.