Pre-Approval Experience in Stage B2 Preclinical MMVD: Clinical findings/adverse reactions were recorded in two multi-site field studies of dogs diagnosed with Stage B2 preclinical MMVD.
Study 1: In the first study, 363 dogs with Stage B2 preclinical MMVD received at least one dose of VETMEDIN (n=182) or the vehicle control chewable tablets (n=181). Dogs were followed until the development of left-sided CHF, cardiac-related death or euthanasia, or until the end of the study (up to 3 years). Adverse reactions were seen in both treatment groups with many findings associated with MMVD and comorbidities consistent with the age of the enrolled dogs.
Cough was the most frequently reported adverse reaction in this study. This clinical finding is commonly reported in cases of MMVD, and the incidence was similar between treatment groups. Gastrointestinal upset (vomiting and diarrhea) was the most frequently reported non-cardiac adverse reaction associated with VETMEDIN.
Mortality rate, regardless of reason, prior to CHF was similar between the VETMEDIN and the control groups.
Table 1: Cardiac Related Adverse Reactionsa (Study 1)
Adverse Reaction
VETMEDIN
Group (n=182)
Vehicle Control
(n=181)
Cough
39 (21.4%)
42 (23.2%)
Lethargy
16 (8.8%)
13 (7.2%)
Inappetence
14 (7.7%)
13 (7.2%)
Tachypnea/panting
13 (7.1%)
12 (6.6%)
Arrhythmia
7 (3.9%)
3 (1.7%)
Collapseb
4 (2.2%)
2 (1.1%)
Dyspnea
4 (2.2%)
3 (1.7%)
Syncopeb
0 (0.0%)
5 (2.8%)
Table 2: Non-cardiac Adverse Reactions (Study 1)
Adverse Reaction
VETMEDIN
Group (n=182)
Vehicle Control
(n=181)
Musculoskeletal pain
24 (13.2%)
12 (6.6%)
Diarrhea
21 (11.5%)
16 (8.8%)
Vomiting
18 (9.9%)
24 (13.3%)
Seizureb
7 (3.8%)
2 (1.1%)
Pruritus
7 (3.9%)
3 (1.7%)
Lameness
7 (3.9%)
3 (1.7%)
Urinary tract infection
7 (3.9%)
2 (1.1%)
Restlessness
4 (2.2%)
0 (0%)
a These adverse reactions are commonly associated with cardiac disease, although some cases may have non-cardiac causes.
b Most cases of collapse, syncope, and seizure were reported by the owner. These clinical signs can be difficult to differentiate.
Study 2: In the second study, 161 dogs with Stage B2 preclinical MMVD were treated with at least one dose of VETMEDIN. All enrolled dogs were treated with VETMEDIN. The dogs were followed for up to 1 year (365 days), or until the development of left-sided CHF, malignant arrhythmias, syncope, advanced coughing, increased resting respiration rate (RRR), or death.
Adverse reactions identified in this study were similar to the first study with many findings associated with MMVD and age-related comorbidities. Cough was the most frequently reported cardiac related adverse reaction and gastrointestinal upset (vomiting and diarrhea) was the most frequently reported non-cardiac adverse reaction associated with VETMEDIN.
Chordae tendineae rupture occurred in 3 dogs receiving VETMEDIN in Study 2, resulting in the euthanasia of one dog. In Study 1, chordae tendineae rupture was observed in 3 control dogs and in 0 VETMEDIN-treated dogs.
In Study 2, 14 VETMEDIN-treated dogs died or were euthanized by Day 365; 8 for cardiac related reasons and 6 for reasons unrelated to MMVD or treatment with VETMEDIN.
Table 3: Cardiac Related Adverse Reactionsa (Study 2)
Adverse Reaction
VETMEDIN
(n=161)
Cough
48 (29.8%)
Inappetence
30 (18.6%)
Lethargy
25 (15.5%)
Tachypnea/panting
17 (10.6%)
Arrhythmia
13 (8.1%)
Dyspnea
6 (3.7%)
Syncopeb
5 (3.1%)
Collapseb
2 (1.2%)
Table 4: Non-cardiac Adverse Reactions (Study 2)
Adverse Reaction
VETMEDIN
(n=161)
Vomiting
59 (36.6%)
Diarrhea
53 (32.9%)
Musculoskeletal pain
12 (7.5%)
Lameness
10 (6.2%)
Dermal mass
9 (5.6%)
Polydipsia
9 (5.6%)
Pruritus
7 (4.3%)
Polyuria
6 (3.7%)
Urinary tract infection
6 (3.7%)
Restlessness
4 (2.5%)
Seizureb
3 (1.9%)
a These adverse reactions are commonly associated with cardiac disease, although some cases may have non-cardiac causes.
b Most cases of collapse, syncope, and seizure were reported by the owner. These clinical signs can be difficult to differentiate.
Pre-Approval Experience in Clinical MMVD or DCM: In a separate study, clinical findings/adverse reactions were recorded in a 56-day field study of dogs with CHF due to MMVD (256 dogs) or DCM (99 dogs). Dogs were treated with either VETMEDIN (175 dogs) or the active control enalapril maleate (180 dogs). Dogs in both treatment groups received additional background cardiac therapy (See Effectiveness for details and the difference in digoxin administration between treatment groups).
The VETMEDIN group had the following incidence (percent of dogs with at least one occurrence) of common adverse reactions/new clinical findings (not present in a dog prior to beginning study treatments). Incidence was similar in the active control group. The incidence of renal failure was higher in the active control group (4%) compared to the VETMEDIN group (1%).
Table 5: Adverse Reactions (Clinical MMVD or DCM)
Adverse Reaction
VETMEDIN
(n=175)
Poor appetite
67 (38%)
Lethargy
58 (33%)
Diarrhea
53 (30%)
Dyspnea
51 (29%)
Azotemia
25 (14%)
Weakness/ataxia
23 (13%)
Pleural effusion
18 (10%)
Syncope
16 (9%)
Cough
12 (7%)
Sudden death
11 (6%)
Ascites
11 (6%)
Heart Murmur
5 (3%)
Adverse reactions/new clinical findings were seen in both treatment groups and were potentially related to CHF, the therapy of CHF, or both. The following adverse reactions/new clinical findings are listed according to body system and are not in order of prevalence: CHF death, sudden death, chordae tendineae rupture, left atrial tear, arrhythmias overall, tachycardia, syncope, weak pulses, irregular pulses, increased pulmonary edema, dyspnea, increased respiratory rate, coughing, gagging, pleural effusion, ascites, hepatic congestion, decreased appetite, vomiting, diarrhea, melena, weight loss, lethargy, depression, weakness, collapse, shaking, trembling, ataxia, seizures, restlessness, agitation, pruritus, increased water consumption, increased urination, urinary accidents, azotemia, dehydration, abnormal serum electrolyte, protein, and glucose values, mild increases in serum hepatic enzyme levels, and mildly decreased platelet counts.
See Table 6 for mortality due to CHF (including euthanasia, natural death, and sudden death) and for the development of new arrhythmias (not present in a dog prior to beginning study treatments) by treatment group and type of heart disease (MMVD or DCM) in the 56-day field study.
Table 6: CHF Death and New Arrhythmias in the 56-Day Field Study
VETMEDIN
Group
Active Control Group
Dogs that died due to CHF
14.3%
n = 175
14.4%
n = 180
9 of 126 dogs with MMVD
16 of 130 dogs with MMVD
16 of 49 dogs with DCM
10 of 50 dogs with DCM
Dogs that developed new arrhythmias
a
39.4%
n = 175
45.0%
n = 180
45 of 126 dogs with MMVD
59 of 130 dogs with MMVD
24 of 49 dogs with DCM
22 of 50 dogs with DCM
a New arrhythmias included supraventricular premature beats and tachycardia, atrial fibrillation, atrioventricular block, sinus bradycardia, ventricular premature beats and tachycardia, and bundle branch block.
Following the 56-day masked field study, 137 dogs in the VETMEDIN group were allowed to continue on VETMEDIN in an open-label extended-use study without restrictions on concurrent therapy. The adverse reactions/new clinical findings in the extended-use study were consistent with those reported in the 56-day study, with the following exception: One dog in the extended-use study developed acute cholestatic liver failure after 140 days on VETMEDIN and furosemide.
Post-Approval Experience (2023): The following adverse events are based on post-approval adverse drug experience reporting for VETMEDIN. Not all adverse events are reported to FDA/CVM. It is not always possible to reliably estimate the adverse event frequency or establish a causal relationship to product exposure using these data.
The following adverse events reported in dogs, are listed in decreasing order of reporting frequency:
Diarrhea, lethargy, anorexia, emesis, cough, tachycardia, ataxia, dyspnea, convulsion, elevated liver enzymes (ALT, ALP), increased BUN and/or creatinine, tremors, hyperactivity, pruritus, syncope, allergic reactions (including allergic edema/facial edema, erythema, and hives), hypotension, hypertension, coagulation abnormalities (including thrombocytopenia, hemorrhage and petechia), and hyperglycemia (with or without diabetes mellitus). Death has been reported in some cases.
Contact Information: To report suspected adverse reactions, to obtain a Safety Data Sheet (SDS), or for technical assistance, contact Boehringer Ingelheim Animal Health USA Inc. at 1-888-637-4251. For additional information about adverse drug experience reporting for animal drugs, contact the FDA at 1-888-FDA-VETS or at www.fda.gov/reportanimalae.
Vetmedin® (pimobendan) Chewable Tablets
Pre-Approval Experience in Clinical MMVD or DCM: Clinical findings/adverse reactions were recorded in a 56-day field study of dogs with CHF due to MMVD (256 dogs) or DCM (99 dogs). Dogs were treated with either pimobendan (175 dogs) or the active control enalapril maleate (180 dogs). Dogs in both treatment groups received additional background cardiac therapy (See Effectiveness for details and the difference in digoxin administration between treatment groups).
The pimobendan group had the following incidence (percent of dogs with at least one occurrence) of common adverse reactions/new clinical findings (not present in a dog prior to beginning study treatments). Incidence was similar in the active control group. The incidence of renal failure was higher in the active control group (4%) compared to the pimobendan group (1 %).
Table 1: Adverse Reactions (Clinical MMVD or DCM)
Adverse Reaction
Pimobendan (n=175)
Poor appetite
67 (38%)
Lethargy
58 (33%)
Diarrhea
53 (30%)
Dyspnea
51 (29%)
Azotemia
25 (14%)
Weakness/ataxia
23(13%)
Pleural effusion
18 (10%)
Syncope
16 (9%)
Cough
12 (7%)
Sudden death
11 (6%)
Ascites
11 (6%)
Heart Murmur
5 (3%)
Adverse reactions/new clinical findings were seen in both treatment groups and were potentially related to CHF, the therapy of CHF, or both. The following adverse reactions/new clinical findings are listed according to body system and are not in order of prevalence: CHF death, sudden death, chordae tendineae rupture, left atrial tear, arrhythmias overall, tachycardia, syncope, weak pulses, irregular pulses, increased pulmonary edema, dyspnea, increased respiratory rate, coughing, gagging, pleural effusion, ascites, hepatic congestion, decreased appetite, vomiting, diarrhea, melena, weight loss, lethargy, depression, weakness, collapse, shaking, trembling, ataxia, seizures, restlessness, agitation, pruritus, increased water consumption, increased urination, urinary accidents, azotemia, dehydration, abnormal serum electrolyte, protein, and glucose values, mild increases in serum hepatic enzyme levels, and mildly decreased platelet counts.
See Table 2 for mortality due to CHF (including euthanasia, natural death, and sudden death) and for the development of new arrhythmias (not present in a dog prior to beginning study treatments) by treatment group and type of heart disease (MMVD or DCM) in the 56-day field study.
Table 2: CHF Death and New Arrhythmias in the 56-Day Field Study
Dogs that died
due to CHF
Pimobendan Group
Active Control Group
14.3%
n = 175
14.4%
n = 180
9 of 126 dogs with MMVD
16 of 130 dogs with MMVD
16 of 49 dogs with DCM
10 of 50 dogs with DCM
Dogs that
developed
new arrhythmiasa
39.4%
n = 175
45.0%
n = 180
45 of 126 dogs with MMVD
59 of 130 dogs with MMVD
24 of 49 dogs with DCM
22 of 50 dogs with DCM
a New arrhythmias included supraventricular premature beats and tachycardia, atrial fibrillation, atrioventricular block, sinus bradycardia, ventricular premature beats and tachycardia, and bundle branch block.
Following the 56-day masked field study, 137 dogs in the pimobendan group were allowed to continue on pimobendan in an open-label extended-use study without restrictions on concurrent therapy. The adverse reactions/new clinical findings in the extended-use study were consistent with those reported in the 56-day study, with the following exception: One dog in the extended-use study developed acute cholestatic liver failure after 140 days on pimobendan and furosemide.
Pimobendan Chewable Tablets
In a controlled multi-center field study, 363 dogs with preclinical MMVD (Stage B2 MMVD, 2019 ACVIM Consensus Statement) received at least one dose of VETMEDIN-CA1 (n=182) or the placebo control chewable tablets (n=181) for up to 1563 days. During this long-term study, dogs were followed until the development of congestive heart failure (CHF). Adverse reactions were seen in both treatment groups with many findings associated with the progression of MMVD and comorbidities consistent with the age of the enrolled dogs.
The median time to the primary endpoint (development of left-sided CHF or cardiac death/euthanasia) was 38% longer in the VETMEDIN-CA1 group. Despite the longer duration on study, the incidence of reported adverse reactions was similar between treatment groups.
Cough was the most frequently reported adverse reaction. This clinical finding is commonly reported in cases of MMVD and the incidence was similar between treatment groups. Lethargy, inappetence, tachypnea, collapse, arrhythmia, and syncope may also be associated with the progression of MMVD and were reported in dogs receiving VETMEDIN-CA1.
Adverse reactions not related to disease progression in dogs receiving VETMEDIN-CA1 included diarrhea, vomiting, pain, lameness, arthritis, urinary tract infection, and seizure.
Mortality rate, regardless of reason, prior to CHF was similar between the VETMEDIN-CA1 and the control groups.
Contact Information: To report suspected adverse reactions, to obtain a Safety Data Sheet (SDS), or for technical assistance, contact Boehringer Ingelheim Animal Health USA Inc. at 1-888-637-4251. For additional information about reporting adverse drug experiences for animal drugs, contact FDA at 1-888-FDA-VETS or at www.fda.gov/reportanimalae.
Vetmedin®-CA1 (pimobendan)Chewable Tablets