Pimobendan: what the FDA reviewed for dog products

Pimobendan Chewable Tablets NADA 200-728, Original approval, April 25, 2024; sponsor Cronus Pharma Specialities India Private Ltd.; species: Dogs; foi_id 15345; FDA PDF

Indication

Management of the signs of mild, moderate, or severe congestive heart failure in dogs due to clinical MMVD or DCM; for use with concurrent CHF therapy

Dose regimen

0.5 mg/kg/day (0.23 mg/lb/day) total daily dose, Oral (chewable tablets), Divided into 2 portions (not necessarily equal) approximately 12 hours apart, Chronic; dosed to nearest half-tablet

Pimomedin™ should be administered orally at a total daily dose of 0.23 mg/lb (0.5 mg/kg) body weight, using a suitable combination of whole or half tablets. The total daily dose should be divided into 2 portions that are not necessarily equal, and the portions should be administered approximately 12 hours apart (i.e., morning and evening).

Pharmacokinetics

Effectiveness

ANADA blood-level bioequivalence study only: GLP, randomized, masked, two-period, two-sequence, single-dose crossover (7-day washout) of generic 5 mg vs Vetmedin 5 mg chewable tablets in fasted dogs; biowaiver for 1.25, 2.5 and 10 mg strengths by dissolution; no clinical effectiveness or safety study; n = 40; primary endpoint: 90% CI of geometric mean ratios (generic:RLNAD) for CMAX and AUC within 0.80-1.25; result: Bioequivalent: ratio 1.03 (AUC; 90% CI 0.89-1.21) and 1.01 (CMAX; 90% CI 0.84-1.22)

Study Animals: 40 intact male beagle dogs, 1-5 years of age Experimental Design: A randomized, masked, two-period, two-sequence, single-dose crossover study conducted according to Good Laboratory Practice for Nonclinical Laboratory Studies.

Extraction notes: Generic (ANADA) summary: no effectiveness or target animal safety studies are required or reported; safety/effectiveness rely on the RLNAD Vetmedin (NADA 141-273). Only the in vivo bioequivalence study is summarized (Table II.1 values quoted). No serious adverse events were reported in the BE study; adverse_reactions left empty.

Vetmedin® NADA 141-273, Original approval, April 30, 2007; sponsor Boehringer lngelheim Animal Health USA, Inc.; species: Dogs; foi_id 832; FDA PDF

Indication

Management of the signs of mild, moderate, or severe (modified NYHA Class II, III, or IV) congestive heart failure in dogs due to atrioventricular valvular insufficiency (AVVI) or dilated cardiomyopathy (DCM), with concurrent CHF therapy as appropriate

Dose regimen

0.5 mg/kg/day (0.23 mg/lb/day) total daily dose, Oral (chewable tablets), Total daily dose divided into 2 portions (not necessarily equal) approximately 12 hours apart, Chronic; dosed to nearest half-tablet; with concurrent CHF therapy (e.g., furosemide) as appropriate

VETMEDIN should be administered orally at a total daily dose of 0.23 mg/lb (0.5 mg/kg) body weight, using a suitable combination of whole or half tablets. The total daily dose should be divided into 2 portions that are not necessarily equal, and the portions should be administered approximately 12 hours apart (i.e., morning and evening).

Target-animal safety

dose multiples 0X, 1X (0.5 mg/kg/day), 3X (1.5 mg/kg/day), 5X (2.5 mg/kg/day); duration 180 days (6 months), total daily dose given in 2 doses/day; animals 24.

Study Design : Laboratory safety study, randomized and masked 1) This 6-month oral safety study was conducted in accordance with the Good Laboratory Practice Regulations (GLPs). 2) Study Animals : 24 healthy Beagles, 12 to 18 months of age and 8.7 to 15.3 kg body weight, 6 dogs per group (3 males and 3 females)

Effectiveness

Multi-site (22 US sites), double-masked, randomized, non-inferiority field study of VETMEDIN 0.5 mg/kg/day vs active control enalapril maleate, 56 days, furosemide as needed; 355 dogs enrolled, 268 cases (136 VETMEDIN, 132 control) in the effectiveness data base; n = 134 VETMEDIN and 131 active control evaluable for Treatment Success at Day 29; primary endpoint: Treatment Success at Day 29 (2 of 3: decreased Heart Insufficiency Score, decreased Pulmonary Edema Score, Overall Clinical Effectiveness score 1-3); non-inferiority vs enalapril; result: VETMEDIN non-inferior to enalapril: Treatment Success Day 29 80.7% vs 76.3% (difference 4.5, one-sided lower 95% CL -3.9)

The results show that VETMEDIN was non-inferior to active control. See Table 5. Table 5: Success Rates for Effectiveness Variables, by Treatment Group Success Ratesa (% of Dogs) Variable (Versus Day 1) VETMEDIN Active Control Difference and Lower 95% Confidence Limit Treatment Success Day 29 80.7 SEb = 3.7 (nb=134) 76.3 SE = 4.0 (n=131) 4.5 SE = 5.1 L95%CLc = -3.9

Adverse reactions

Extraction notes: No pharmacokinetic parameters (half-life, Cmax, AUC etc.) are reported in this 2007 summary; only LV dP/dtmax pharmacodynamics. Target animal safety taken from the 6-month oral study (0X/1X/3X/5X, 24 Beagles, 180 days); a 4-week IV dose-tolerance study (0, 0.5, 2, 8 mg/kg/day IV, 30 Beagles) is also reported and showed dose-dependent cardiac lesions. Effectiveness n: 355 enrolled, 268 cases evaluable (136 VETMEDIN, 132 active control); n_dogs gives the Table 5 Day-29 denominators because that span carries the result. Adverse reactions are prevalence in the VETMEDIN safety group (175 dogs) from the pivotal field study; control percentages are not tabulated ('Prevalence was similar in the active control group').

Vetmedin® NADA 141-273, Supplemental approval, December 19, 2025; sponsor Boehringer lngelheim Animal Health USA, Inc.; species: Dogs; foi_id 17792; FDA PDF

Indication

Added by this supplement: delay of onset of congestive heart failure in dogs with Stage B2 preclinical myxomatous mitral valve disease (asymptomatic MMVD with moderate or loud mitral murmur and cardiomegaly). Existing indications: management of signs of mild, moderate or severe CHF due to clinical MMVD or DCM, with concurrent therapy.

Dose regimen

0.23 mg/lb (0.5 mg/kg) total daily dose, oral (chewable tablet), divided into 2 portions approximately 12 hours apart, chronic; unchanged from the original approval (field studies dosed 0.5 mg/kg/day with 2.5 mg tablets by weight band)

This supplemental approval does not change the previously approved Vetmedin® total daily dose of 0.23 mg/lb (0.5 mg/kg) divided into 2 portions administered approximately 12 hours apart.

Effectiveness

Two multi-site field studies: (1) EPIC study 2009045, randomized 1:1, vehicle-controlled, masked, GCP, 36 sites in the US and internationally, dogs 4.1-15 kg with Stage B2 MMVD (murmur >= 3/6, LA/Ao >= 1.6, LVIDDN >= 1.7, VHS > 10.5), Vetmedin 0.5 mg/kg/day vs vehicle, time-to-event with interim analysis (corroborative); (2) US study 2019035, single-arm, open-label, historically controlled (EPIC control subset), 161 dogs with LA/Ao >= 1.8 treated up to 365 days (pivotal); n = 363 enrolled (353 effectiveness population) in EPIC; primary endpoint: EPIC: time from first treatment to composite of left-sided CHF (radiographically verified by masked endpoint committee), cardiac-related euthanasia or presumed cardiac death. US study: individual treatment success (no CHF, cardiac death, or arrhythmia/syncope/cough/increased RRR requiring therapy by Day 365); result: EPIC final analysis: 73/173 Vetmedin vs 91/170 control dogs reached the primary endpoint; median time to endpoint 1,127 days vs 732 days (difference 395 days), log-rank p = 0.0008, hazard ratio 0.591 (95% CI 0.434-0.805); median time to verified CHF 1,231 vs 806 days; median survival 1,015 vs 878 days. US study: success rate 79.2% (95% CI 70.3-85.9%) in 125 dogs, lower bound above the 54% threshold

Study Animals: A total of 363 client-owned dogs were enrolled in the study; 40.2% of the dogs were female (intact and spayed) and 59.8% were male (intact and neutered). The effectiveness population consisted of 353 dogs of various breeds.

Adverse reactions

Extraction notes: Supplemental approval (December 2025) adding the Stage B2 preclinical MMVD indication. No target animal safety studies were required (refers to the 2007 original FOI summary) and no PK data are presented. The EPIC study did not meet certain characteristics of an adequate and well-controlled study and was considered corroborative to the single-arm US study; the EPIC randomized results are recorded as the effectiveness result because they are the controlled comparison, with the US study result alongside. Adverse reaction quotes are flattened Tables II.5/II.6 rows (term, Vetmedin count (%), vehicle count (%)). Other EPIC rows: tachypnea/panting 13 (7.1%) vs 12 (6.6%), arrhythmia 7 (3.9%) vs 3 (1.7%), seizure 7 (3.8%) vs 2 (1.1%), syncope 0 vs 5 (2.8%). US study (n=161): vomiting 59 (36.6%), diarrhea 53 (32.9%), cough 48 (29.8%); chordae tendineae rupture in three treated dogs; 14 deaths by Day 365 (9 cardiac).

Vetmedin® Solution NADA 141-575, Original approval, February 13, 2024; sponsor Boehringer lngelheim Animal Health USA, Inc.; species: Dogs; foi_id 15024; FDA PDF

Indication

Management of the signs of mild, moderate, or severe congestive heart failure in dogs due to clinical myxomatous mitral valve disease (MMVD) or dilated cardiomyopathy (DCM); for use with concurrent CHF therapy

Dose regimen

0.5 mg/kg/day (0.23 mg/lb/day) total daily dose, Oral (1.5 mg/mL solution, directly into the mouth; do not mix into food), Divided into 2 equal portions approximately 12 hours apart, Chronic; syringe calibrated to body weight in pounds

Vetmedin® Solution should be administered orally at a total daily dose of 0.23 mg/lb (0.5 mg/kg) body weight. The total daily dose should be divided into 2 equal portions administered approximately 12 hours apart (i.e., morning and evening).

Pharmacokinetics

Effectiveness

Bioequivalence bridge only: GLP, randomized (blocked by weight), masked, four-period, two-sequence, single-dose, full replicate crossover of Vetmedin Solution vs Vetmedin chewable tablets (5 mg pimobendan) in adult Beagles; no new clinical effectiveness study (refers to NADA 141-273); n = 12 male/12 female adult Beagles (twenty-four); primary endpoint: Bioequivalence for Cmax and AUClast (RSABE method; point estimate within 0.80-1.25 and 95% upper bound < 0); result: Bioequivalence established: GMR 0.927 (Cmax) and 0.853 (AUClast); 95% upper bounds -0.153 and -0.029

Study Animals: Twenty-four male and female, adult Beagle dogs (12 male/12 female) with a body weight range of 9.0 to 16.5 kg (determined on Day -1) were enrolled in this study. Animals were randomly allocated to two groups, 12 animals per group. Experimental Design: This study was conducted in compliance with good laboratory practice (GLP) regulations. The study was designed as a randomized (blocked by weight), masked, four-period, two-sequence, single-dose, full replicative cross-over design (Table II.1).

Extraction notes: Supplemental-type original approval of a new formulation: effectiveness and target animal safety are established by bioequivalence to Vetmedin chewable tablets (NADA 141-273); no field study and no margin-of-safety study in this summary, so target_animal_safety is null. PK values are from Table II.2 (geometric means except median Tmax). No treatment-related adverse reactions were noted in the BE study, so adverse_reactions is empty.

Vetmedin® Solution NADA 141-575, Supplemental approval, January 15, 2026; sponsor Boehringer lngelheim Animal Health USA, Inc.; species: Dogs; foi_id 17909; FDA PDF

Indication

Added indication: delay of onset of congestive heart failure in dogs with Stage B2 preclinical MMVD (asymptomatic MMVD with moderate or loud mitral murmur and cardiomegaly); previously approved for management of signs of mild, moderate or severe CHF due to clinical MMVD or DCM.

Dose regimen

0.23 mg/lb (0.5 mg/kg) body weight total daily dose, Oral (1.5 mg/mL solution, directly into the mouth; do not mix into food), Divided into 2 equal portions approximately 12 hours apart (morning and evening), Syringe calibrated to the dog's nearest weight in pounds

Vetmedin® Solution should be administered orally at a total daily dose of 0.23 mg/lb (0.5 mg/kg) body weight. The total daily dose should be divided into 2 equal portions administered approximately 12 hours apart (i.e., morning and evening).

Effectiveness

Cross-reference only (no new study): two multisite field studies with Vetmedin® chewable tablets (NADA 141-273 supplemental FOI, December 19, 2025) plus the bioequivalence study of the solution vs tablets (NADA 141-575 original FOI, February 13, 2024).; result: FDA did not require prospective safety and effectiveness studies; effectiveness for the new indication is supported by the tablet field studies at the same dose and by bioequivalence of the solution to the tablets.

The effectiveness of Vetmedin® Solution (pimobendan oral solution) for the delay of onset of CHF in dogs with Stage B2 preclinical MMVD is based on results from two multisite field studies conducted with Vetmedin® (pimobendan) chewable tablets.

Extraction notes: Supplemental approval adding an indication; contains no new studies, PK, target animal safety or adverse reaction data. Effectiveness entry is a cross-reference statement, not a study. Category II supplement; three years of exclusivity for the new indication.

Vetmedin® NADA 141-273, Supplemental approval, June 16, 2022; sponsor Boehringer lngelheim Animal Health USA, Inc.; species: Dogs; foi_id 18231; FDA PDF

Indication

Delay of onset of congestive heart failure in dogs with Stage B2 preclinical myxomatous mitral valve disease (MMVD): asymptomatic MMVD with a moderate or loud mitral murmur due to mitral regurgitation and cardiomegaly (conditional approval).

Dose regimen

0.23 mg/lb (0.5 mg/kg) body weight total daily dose, Oral (chewable tablets), Total daily dose divided into 2 portions (not necessarily equal) given approximately 12 hours apart (morning and evening), Chronic administration; scored tablets, dose provided to the nearest half-tablet increment

Vetmedin®-CA1 should be administered orally at a total daily dose of 0.23 mg/lb (0.5 mg/kg) body weight, using a suitable combination of whole or half tablets. The total daily dose should be divided into 2 portions that are not necessarily equal, and the portions should be administered approximately 12 hours apart (i.e., morning and evening).

Effectiveness

EPIC (Study No. 2009045): multi-center (US and international), randomized 1:1, vehicle-controlled, masked field study in client-owned dogs (4.1-15.0 kg, 6-17 years) with Stage B2 preclinical MMVD; Vetmedin®-CA1 0.5 mg/kg/day vs identical vehicle tablet; Kaplan-Meier/log-rank and Cox model; pre-specified O'Brien-Fleming interim analysis led to early termination for effectiveness (March 2015).; n = 353 (effectiveness population: 178 pimobendan, 175 control); primary endpoint: Time from first treatment to composite of left-sided congestive heart failure (radiographically confirmed by masked endpoint committee), cardiac-related euthanasia, or presumed cardiac death; result: Median time to primary endpoint 1228 days (pimobendan) vs 761 days (control), difference 467 days (15.6 months); log-rank p = 0.0028; hazard ratio 0.6259 (95% CI 0.4589-0.8537). Secondary: median survival 1059 vs 889 days; decreased LVIDDN at Day 35.

Of the 353 dogs included in the effectiveness population in the final analysis, 74 of 178 dogs in the pimobendan group and 88 of 175 dogs in the control group reached the primary endpoint. There were 59 cases with verified congestive heart failure and 15 cases of death or euthanasia for cardiac disease related reason in the pimobendan group, and 76 cases with verified congestive heart failure and 12 cases of death or euthanasia for cardiac disease related reason in the control group. In the final analysis, the log-rank test for the comparison of the survival curves between the two treatment groups had a p-value of 0.0028. The median (95% confidence interval) time to the primary endpoint was 1228 (856, high end not estimable) days in the pimobendan group, and 761 (637 – 875) days in the control group. This translates to a difference of 467 days (15.6 months) in the median time to the primary endpoint in favor of the pimobendan group. The hazard ratio (95% confidence interval) from the Cox Proportional hazard model was 0.6259 (0.4589 - 0.8537).

Adverse reactions

Extraction notes: Summary is for conditional approval application 141-556 (Vetmedin®-CA1), catalogued under NADA 141-273. Safety population 363 dogs (182 pimobendan, 181 control). No adverse-reaction incidence table is given (qualitative only, so treated/control left null). No PK data; target animal safety is cross-referenced to the Vetmedin® NADA 141-273 studies (same dosage), so target_animal_safety is null.