Vetmedin-CA1: Product Information

VETMEDIN-CA1- pimobendan tablet, chewable
Boehringer Ingelheim Animal Health USA Inc.

Cardiac drug for oral use in dogs only

Caution:

Federal law restricts this drug to use by or on the order of a licensed veterinarian. Use only as directed.

It is a violation of Federal law to use this product other than as directed in the labeling.

Conditionally approved by FDA pending a full demonstration of effectiveness under application number 141-556.

Description:

VETMEDIN-CA1 (pimobendan) is supplied as oblong half-scored chewable tablets containing 1.25 or 5 mg pimobendan per tablet. Pimobendan, a benzimidazole-pyridazinone derivative, is a non-sympathomimetic, non-glycoside inotropic drug with vasodilatative properties. Pimobendan exerts a stimulatory myocardial effect by a dual mechanism of action consisting of an increase in calcium sensitivity of cardiac myofilaments and inhibition of phosphodiesterase (Type III). Pimobendan exhibits

vasodilating activity by inhibiting phosphodiesterase III activity. The chemical name of pimobendan is 4,5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazole-5-yl]-5-methyl-3(2H)-pyridazinone. The structural formula of pimobendan is:

Picture of structural formula of pimobendan
(click image for full-size original)

Indications:

VETMEDIN-CA1 (pimobendan) is indicated for the delay of onset of congestive heart failure in dogs with Stage B2 preclinical myxomatous mitral valve disease (2019 ACVIM Consensus Statement1).

Stage B2 preclinical myxomatous mitral valve disease (MMVD) refers to dogs with asymptomatic MMVD that have a moderate or loud mitral murmur due to mitral regurgitation and cardiomegaly.

Dosage and Administration:

Always provide the Client Information Sheet to the dog owner with each prescription. 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). The tablets are scored, and the calculated dosage should be provided to the nearest half tablet increment.

Contraindications:

Do not administer VETMEDIN-CA1 in cases of hypertrophic cardiomyopathy, aortic stenosis, or any other clinical condition where an augmentation of cardiac output is inappropriate for functional or anatomical reasons.

Do not administer VETMEDIN-CA1 to dogs with Stage A or B1 preclinical MMVD (2019 ACVIM Consensus Statement) due to the risk of cardiac pathology associated with exaggerated hemodynamic responses to VETMEDIN-CA1.

Warnings:

User Safety Warnings: Not for use in humans. Keep this and all medications out of reach of children. Consult a physician in case of accidental ingestion by humans.

Animal Safety Warnings: Keep VETMEDIN-CA1 in a secure location out of reach of dogs, cats, and other animals to prevent accidental ingestion or overdose.

At 3 and 5 times the recommended dosage, administered over a 6-month period of time, pimobendan caused an exaggerated hemodynamic response in the normal dog heart, which was associated with cardiac pathology (See Target Animal Safety).

Precautions:

For use only in dogs with preclinical MMVD that have a moderate or loud mitral murmur due to mitral regurgitation and cardiomegaly (Stage B2 MMVD, 2019 ACVIM Consensus Statement). A diagnosis of MMVD should be made by means of a comprehensive physical and cardiac examination which should include radiography and echocardiography. Stage B2 cardiomegaly is diagnosed based on meeting all three of the following criteria:

• Radiographic vertebral heart score (VHS) >10.5, and

• Echocardiographic left atrium/aorta ratio (LA/Ao ratio) ≥1.6, and

• Echocardiographic left ventricular internal diastolic diameter normalized to body weight (LVIDDN) ≥1.7.

Echocardiographic examination is recommended in all cases to diagnose MMVD and confirm cardiomegaly. If therapy is initiated prior to the development of cardiomegaly, treated dogs are at risk for cardiac pathology associated with exaggerated hemodynamic responses to VETMEDIN-CA1.

If only radiographic examination is possible, cardiomegaly may be diagnosed in cases where the VHS ≥11.5 and the vertebral left atrial size (VLAS) ≥3.01,2. If radiographic cardiomegaly does not meet both of these criteria, an echocardiogram should be performed prior to the initiation of therapy with VETMEDIN-CA1.

VETMEDIN-CA1 has not been evaluated in dogs receiving concomitant heart medications.

The safety of VETMEDIN-CA1 has not been established in dogs with asymptomatic heart disease caused by etiologies other than MMVD. The safe use of VETMEDIN-CA1 has not been evaluated in dogs younger than 6 months of age, dogs with congenital heart defects, dogs with diabetes mellitus or other serious metabolic diseases, dogs used for breeding, or pregnant or lactating bitches.

Adverse Reactions:

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 http://www.fda.gov/reportanimalae.

Information for Dog Owners:

Always provide the Client Information Sheet with each prescription and review it with the dog owner or person responsible for care of the dog. Advise dog owners about signs of disease progression and possible adverse reactions with use of VETMEDIN-CA1.

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-CA1, 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-CA1 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.

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