Vetmedin: Product Information (Page 2 of 3)

Clinical Pharmacology:

Pimobendan is oxidatively demethylated to a pharmacologically active metabolite which is then conjugated with sulfate or glucuronic acid and excreted mainly via feces. The mean extent of protein binding of pimobendan and the active metabolite in dog plasma is >90%. Following a single oral administration of 0.25 mg/kg VETMEDIN tablets the maximal mean (± 1 SD) plasma concentrations (Cmax) of pimobendan and the active metabolite were 3.09 (0.76) ng/mL and 3.66 (1.21) ng/mL, respectively. Individual dog Cmax values for pimobendan and the active metabolite were observed 1 to 4 hours post-dose (mean: 2 and 3 hours, respectively). The total body clearance of pimobendan was approximately 90 mL/min/kg, and the terminal elimination half-lives of pimobendan and the active metabolite were approximately 0.5 hours and 2 hours, respectively. Plasma levels of pimobendan and active metabolite were below quantifiable levels by 4 and 8 hours after oral administration, respectively. The steady-state volume of distribution of pimobendan is 2.6 L/kg indicating that the drug is readily distributed into tissues. Food decreased the bioavailability of an aqueous solution of pimobendan, but the effect of food on the absorption of pimobendan from VETMEDIN tablets is unknown.

In normal dogs instrumented with left ventricular (LV) pressure transducers, pimobendan increased LV dP/dtmax (a measure of contractility of the heart) in a dose dependent manner between 0.1 and 0.5 mg/kg orally. The effect was still present 8 hours after dosing. There was a delay between peak blood levels of pimobendan and active metabolite and the maximum physiologic response (peak LV dP/dtmax). Blood levels of pimobendan and active metabolite began to drop before maximum contractility was seen. Repeated oral administration of pimobendan did not result in evidence of tachyphylaxis (decreased positive inotropic effect) or drug accumulation (increased positive inotropic effect). Laboratory studies indicate that the positive inotropic effect of pimobendan may be attenuated by the concurrent use of a β-adrenergic blocker or a calcium channel blocker.

Effectiveness:

In a double-masked, multi-site, 56-day field study, 355 dogs with modified New York Heart Association‡ (NYHA) Class II, III, or IV CHF due to MMVD or DCM were randomly assigned to either the active control (enalapril maleate) or the VETMEDIN (pimobendan) treatment group. Of the 355 dogs, 52% were male and 48% were female; 72% were diagnosed with MMVD and 28% were diagnosed with DCM; 34% had Class II, 47% had Class III, and 19% had Class IV CHF. Dogs ranged in age and weight from 1 to 17 years and 3.3 to 191 lbs, respectively. The most common breeds were mixed breed, Doberman Pinscher, Cocker Spaniel, Miniature/Toy Poodle, Maltese, Chihuahua, Miniature Schnauzer, Dachshund, and Cavalier King Charles Spaniel. The 180 dogs (130 MMVD, 50 DCM) in the active control group received enalapril maleate (0.5 mg/kg once or twice daily), and all but 2 received furosemide. Per protocol, all dogs with DCM in the active control group received digoxin. The 175 dogs (126 MMVD, 49 DCM) in the VETMEDIN group received pimobendan (0.5 mg/kg/day divided into 2 portions that were not necessarily equal, and the portions were administered approximately 12 hours apart), and all but 4 received furosemide. Digoxin was optional for treating supraventricular tachyarrhythmia in either treatment group, as was the addition of a b-adrenergic blocker if digoxin was ineffective in controlling heart rate. After initial treatment at the clinic on Day 1, dog owners were to administer the assigned product and concurrent medications for up to 56±4 days.

The determination of effectiveness (treatment success) for each case was based on improvement in at least 2 of the 3 following primary variables: modified NYHA classification, pulmonary edema score by a

masked veterinary radiologist, and the investigator’s overall clinical effectiveness score (based on physical examination, radiography, electrocardiography, and clinical pathology). Attitude, pleural effusion, coughing, activity level, furosemide dosage change, cardiac size, body weight, survival, and owner observations were secondary evaluations contributing information supportive to product effectiveness and safety.

Based on protocol compliance and individual case integrity, 265 cases (134 VETMEDIN, 131 active control) were evaluated for treatment success on Day 29. See Table 2 for effectiveness results.

Table 2: Effectiveness Results for the 56-Day Field Study

VETMEDIN® Group

Active Control Group

Treatment Success on Day 29

80.7%

n = 134

88 of 101 dogs with MMVD

20 of 33 dogs with DCM

76.3%

n = 131

77 of 100 dogs with MMVD

23 of 31 dogs with DCM

Treatment Success on Day 56

71.1%

n = 113

66 of 85 dogs with MMVD

13 of 28 dogs with DCM

67.2%

n = 110

56 of 85 dogs with MMVD

17 of 25 dogs with DCM

No increase in furosemide dose between Day 1 and Day 29

78.3%

n = 130

68.6%

n = 126

At the end of the 56-day study, dogs in the VETMEDIN group were enrolled in an unmasked field study to monitor safety under extended use, without restrictions on concurrent medications.

VETMEDIN was used safely in dogs concurrently receiving furosemide, digoxin, enalapril, atenolol, spironolactone, nitroglycerin, hydralazine, diltiazem, antiparasitic products (including heartworm disease prevention), antibiotics (metronidazole, cephalexin, amoxicillin-clavulanate, fluoroquinolones), topical ophthalmic and otic products, famotidine, theophylline, levothyroxine sodium, diphenhydramine, hydrocodone, metoclopramide, and butorphanol, and in dogs on sodium-restricted diets.

‡The modified NYHA classification was historically used to stage dogs with heart disease.

A dog with modified NYHA Class II heart failure has fatigue, shortness of breath, coughing, etc. apparent when ordinary exercise is exceeded.

A dog with modified NYHA Class III heart failure is comfortable at rest, but exercise capacity is minimal.

A dog with modified NYHA Class IV heart failure has no capacity for exercise and disabling clinical signs are present even at rest.

Palatability:

In a laboratory study, the palatability of VETMEDIN was evaluated in 20 adult female Beagle dogs offered doses twice daily for 14 days. Ninety percent (18 of 20 dogs) voluntarily consumed more than 70% of the 28 tablets offered. Including two dogs that consumed only 4 and 7% of the tablets offered, the average voluntary consumption was 84.2%.

Target Animal Safety:

In a laboratory study, VETMEDIN chewable tablets were administered to 6 healthy Beagles per treatment group at 0 (control), 1, 3, and 5 times the recommended dosage for 6 months. See Table 3 for cardiac pathology results. The cardiac pathology/histopathology noted in the 3X and 5X dose groups is typical of positive inotropic and vasodilator drug toxicity in normal dog hearts, and is associated with exaggerated hemodynamic responses to these drugs. None of the dogs developed signs of heart failure and there was no mortality.

Table 3: Incidence of Cardiac Pathology/Histopathology in the Six-month Safety Study

Severe left ventricular hypertrophy with multifocal subendocardial ischemic lesions

One 3X and two 5X dogsa

Moderate to marked myxomatous thickening of the mitral valves

Three 5X dogs

Myxomatous thickening of the chordae tendineae

One 3X and two 5X dogs

Endocardial thickening of the left ventricular outflow tract

One 1X, two 3X, and two 5X dogs

Left atrial endocardial thickening (jet lesions) in 2 of the dogs that developed murmurs of mitral valve insufficiency

One 3X and one 5X dog

Granulomatous inflammatory lesion in the right atrial myocardium

One 3X dog

a Most of the gross and histopathologic findings occurred in these three dogs

Murmurs of mitral valve insufficiency were detected in one 3X (Day 65) and two 5X dogs (Days 135 and 163). These murmurs (grades II-III of VI) were not associated with clinical signs.

Indirect blood pressure was unaffected by VETMEDIN at the label dose (1X). Mean diastolic blood pressure was decreased in the 3X group (74 mmHg) compared to the control group (82 mmHg). Mean systolic blood pressure was decreased in the 5X group (117 mmHg) compared to the control group (124 mmHg). None of the dogs had clinical signs of hypotension.

On 24-hour Holter monitoring, mean heart rate was increased in the 5X group (101 beats/min) compared to the control group (94 beats/min). Not counting escape beats, the 3X and 5X groups had slightly higher numbers of isolated ventricular ectopic complexes (VEs). The maximum number of non-escape VEs recorded either at baseline or in a control group dog was 4 VEs/24 hours. At either Week 4 or Week 20, three 3X group dogs had maximums of 33, 13, and 10 VEs/24 hours, and two 5X group dogs had maximums of 22 and 9 VEs/24 hours. One 1X group dog with no VEs at baseline had 6 VEs/24 hours at Week 4 and again at Week 20. Second-degree atrioventricular heart block was recorded in one 3X group dog at Weeks 4 and 20, and in one dog from each of the 1X and 5X groups at Week 20. None of the dogs had clinical signs associated with these electrocardiogram changes.

Treatment was associated with small differences in mean platelet counts (decreased in the 3X and 1X groups), potassium (increased in the 5X group), glucose (decreased in the 1X and 3X groups), and maximum blood glucose in glucose curves (increased in the 5X group). All individual values for these variables were within the normal range. Three 1X and one 5X group dogs had mild elevations of alkaline phosphatase (less than two times normal).

Loose stools and vomiting were infrequent and self-limiting.

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