Capricciosa, geniale, eterea, ma anche profonda ed altera, Vittoria Guerrini – oggi più nota con lo pseudonimo prediletto di Cristina Campo – ha attraversato come una cometa ardente la cultura italiana del Novecento. Questa pensatrice – importante ma ancora troppo poco nota – ha lasciato una testimonianza vivida e, per molti versi, unica – anche se ancora poco visibile – di un
Layoutscored and the calculated dosage should beprovided to the nearest half tablet increment.
Contraindications: Vetmedin should not be given
in cases of hypertrophic cardiomyopathy, aorticstenosis, or any other clinical condition where an Caution: Federal law restricts this drug to use by
augmentation of cardiac output is inappropriate or on the order of a licensed veterinarian.
for functional or anatomical reasons.
Description: Vetmedin (pimobendan) is supplied as
Warnings: Only for use in dogs with clinical
oblong half-scored chewable tablets containing evidence of heart failure. At 3 and 5 times the 1.25 or 5 mg pimobendan per tablet. Pimobendan, a benzimidazole-pyridazinone derivative, is a non- 6-month period of time, pimobendan caused sympathomimetic, non-glycoside inotropic drug an exaggerated hemodynamic response in the with vasodilatative properties. Pimobendan exerts normal dog heart, which was associated with a stimulatory myocardial effect by a dual mechanism cardiac pathology (See Animal Safety).
of action consisting of an increase in calcium Human Warnings: Not for use in humans. Keep
sensitivity of cardiac myofilaments and inhibition this and all medications out of reach of children.
of phosphodiesterase (Type III). Pimobendan exhibits Consult a physician in case of accidental ingestion vasodilating activity by inhibiting phosphodiesterase III activity. The chemical name of pimobendan is 4,5-dihydro-6-[2-(4-methoxyphenyl)-1H-benzimidazole- Precautions: The safety of Vetmedin has not been
established in dogs with asymptomatic heartdisease or in heart failure caused by etiologies other than AVVI or DCM. The safe use of Vetmedinhas not been evaluated in dogs younger than6 months of age, dogs with congenital heartdefects, dogs with diabetes mellitus or otherserious metabolic diseases, dogs used forbreeding, or pregnant or lactating bitches.
Adverse Reactions: Clinical findings/adverse
Indications: Vetmedin (pimobendan) is indicated
reactions were recorded in a 56-day field study of dogs with congestive heart failure (CHF) due moderate, or severe (modified NYHA Class IIa, to AVVI (256 dogs) or DCM (99 dogs). Dogs were IIIb, or IVc) congestive heart failure in dogs due treated with either Vetmedin (175 dogs) or the to atrioventricular valvular insufficiency (AVVI) active control enalapril maleate (180 dogs). Dogs or dilated cardiomyopathy (DCM). Vetmedin is in both treatment groups received additional indicated for use with concurrent therapy for background cardiac therapy (See Effectiveness
congestive heart failure (e.g., furosemide, etc.) for details and the difference in digoxin as appropriate on a case-by-case basis.
administration between treatment groups).
a A dog with modified New York Heart Association The Vetmedin group had the following prevalence (NYHA) Class II heart failure has fatigue, shortness (percent of dogs with at least one occurrence) of breath, coughing, etc. apparent when ordinary of common adverse reactions/new clinical findings (not present in a dog prior to beginning studytreatments): poor appetite (38%), lethargy (33%), b A dog with modified NYHA Class III heart failure is diarrhea (30%), dyspnea (29%), azotemia (14%), comfortable at rest, but exercise capacity is minimal.
weakness and ataxia (13%), pleural effusion (10%), c A dog with modified NYHA Class IV heart failure syncope (9%), cough (7%), sudden death (6%), has no capacity for exercise and disabling clinical ascites (6%), and heart murmur (3%). Prevalence was similar in the active control group. The prevalenceof renal failure was higher in the active control group Dosage and Administration: Vetmedin should
(4%) compared to the Vetmedin group (1%).
be administered orally at a total daily dose of0.23 mg/lb (0.5 mg/kg) body weight, using a Adverse reactions/new clinical findings were seen in suitable combination of whole or half tablets. The both treatment groups and were potentially related total daily dose should be divided into 2 portions to CHF, the therapy of CHF, or both. The following that are not necessarily equal, and the portions adverse reactions/new clinical findings are listed should be administered approximately 12 hours according to body system and are not in order apart (i.e., morning and evening). The tablets are of prevalence: CHF death, sudden death, chordae tendineae rupture, left atrial tear, arrhythmias Clinical Pharmacology: Pimobendan is oxidatively
overall, tachycardia, syncope, weak pulses, irregular demethylated to a pharmacologically active pulses, increased pulmonary edema, dyspnea, metabolite which is then conjugated with sulfate increased respiratory rate, coughing, gagging, or glucuronic acid and excreted mainly via feces.
pleural effusion, ascites, hepatic congestion, The mean extent of protein binding of pimobendan decreased appetite, vomiting, diarrhea, melena, and the active metabolite in dog plasma is >90%.
weight loss, lethargy, depression, weakness, Following a single oral administration of 0.25 mg/kg collapse, shaking, trembling, ataxia, seizures, Vetmedin tablets the maximal mean (± 1 SD) plasma restlessness, agitation, pruritus, increased water concentrations (Cmax) of pimobendan and the consumption, increased urination, urinary active metabolite were 3.09 (0.76) ng/ml and accidents, azotemia, dehydration, abnormal serum 3.66 (1.21) ng/ml, respectively. Individual dog Cmax electrolyte, protein, and glucose values, mild values for pimobendan and the active metabolite increases in serum hepatic enzyme levels, and mildly were observed 1 to 4 hours post-dose (mean: 2 and 3 hours, respectively). The total body clearanceof pimobendan was approximately 90 mL/min/kg, See Table 1 for mortality due to CHF (including and the terminal elimination half-lives of pimobendan euthanasia, natural death, and sudden death) and and the active metabolite were approximately for the development of new arrhythmias (not 0.5 hours and 2 hours, respectively. Plasma levels present in a dog prior to beginning study of pimobendan and active metabolite were below treatments) by treatment group and type of heart quantifiable levels by 4 and 8 hours after oral disease (AVVI or DCM) in the 56-day field study.
administration, respectively. The steady-state Table 1: CHF Death and New Arrhythmias
volume of distribution of pimobendan is 2.6 L/kg, in the 56-Day Field Study
indicating that the drug is readily distributed intotissues. Food decreased the bioavailability of an Vetmedin® Group
Active Control Group
aqueous solution of pimobendan, but the effect of food on the absorption of pimobendan from Dogs that
In normal dogs instrumented with left ventricular (LV) pressure transducers, pimobendan increased Dogs that
LV dP/dtmax (a measure of contractility of the developed
heart) in a dose-dependent manner between 0.1 and 0.5 mg/kg orally. The effect was still present 8 hours arrhythmiasa
after dosing. There was a delay between peak bloodlevels of pimobendan and active metabolite and the a New arrhythmias included supraventricular premature beats maximum physiologic response (peak LV dP/dtmax).
and tachycardia, atrial fibrillation, atrioventricular block, sinus Blood levels of pimobendan and active metabolite bradycardia, ventricular premature beats and tachycardia, began to drop before maximum contractility was seen. Repeated oral administration of pimobendan Following the 56-day masked field study, 137 dogs did not result in evidence of tachyphylaxis in the Vetmedin group were allowed to continue (decreased positive inotropic effect) or drug on Vetmedin in an open-label extended-use study accumulation (increased positive inotropic effect).
without restrictions on concurrent therapy. The Laboratory studies indicate that the positive adverse reactions/new clinical findings in the inotropic effect of pimobendan may be attenuated extended-use study were consistent with those by the concurrent use of a ß-adrenergic blocker reported in the 56-day study, with the following exception: One dog in the extended-use study Effectiveness: In a double-masked, multi-site,
developed acute cholestatic liver failure after 56-day field study, 355 dogs with modified NYHA 140 days on Vetmedin and furosemide.
Class II, III, or IV CHF due to AVVI or DCM wererandomly assigned to either the active control In foreign post-approval drug experience reporting, (enalapril maleate) or the Vetmedin (pimobendan) the following additional suspected adverse reactions treatment group. Of the 355 dogs, 52% were male were reported in dogs treated with a capsule and 48% were female; 72% were diagnosed with formulation of pimobendan: hemorrhage, petechia, AVVI and 28% were diagnosed with DCM; 34% had anemia, hyperactivity, excited behavior, erythema, Class II, 47% had Class III, and 19% had Class IV rash, drooling, constipation, and diabetes mellitus.
CHF. Dogs ranged in age and weight from 1 to To report suspected adverse reactions, to obtain 17 years and 3.3 to 191 lb, respectively. The most a Material Safety Data Sheet, or for technical Pinscher, Cocker Spaniel, Miniature/Toy Poodle, At the end of the 56-day study, dogs in the Vetmedin Maltese, Chihuahua, Miniature Schnauzer, Dachshund, group were enrolled in an unmasked field study and Cavalier King Charles Spaniel. The 180 dogs to monitor safety under extended use, without (130 AVVI, 50 DCM) in the active control group restrictions on concurrent medications.
received enalapril maleate (0.5 mg/kg once or Vetmedin was used safely in dogs concurrently twice daily), and all but 2 received furosemide.
receiving furosemide, digoxin, enalapril, atenolol, Per protocol, all dogs with DCM in the active spironolactone, nitroglycerin, hydralazine, diltiazem, control group received digoxin. The 175 dogs antiparasitic products (including heartworm prevention), antibiotics (metronidazole, cephalexin, received pimobendan (0.5 mg/kg/day divided amoxicillin-clavulanate, fluoroquinolones), topical into 2 portions that were not necessarily equal, ophthalmic and otic products, famotidine, theophylline, and the portions were administered approximately levothyroxine sodium, diphenhydramine, hydrocodone, 12 hours apart), and all but 4 received furosemide.
metoclopramide, and butorphanol, and in dogs on Digoxin was optional for treating supraventricular tachyarrhythmia in either treatment group, as wasthe addition of a ß-adrenergic blocker if digoxin Palatability: In a laboratory study, the palatability
was ineffective in controlling heart rate. After initial of Vetmedin was evaluated in 20 adult female treatment at the clinic on Day 1, dog owners were Beagle dogs offered doses twice daily for 14 days.
to administer the assigned product and concurrent Ninety percent (18 of 20 dogs) voluntarily consumed more than 70% of the 28 tablets offered. Includingtwo dogs that consumed only 4 and 7% of the The determination of effectiveness (treatment tablets offered, the average voluntary consumption success) for each case was based on improvement in at least 2 of the 3 following primary variables:modified NYHA classification, pulmonary edema Animal Safety: In a laboratory study, Vetmedin
score by a masked veterinary radiologist, and the chewable tablets were administered to 6 healthy investigator’s overall clinical effectiveness score Beagles per treatment group at 0 (control), 1, 3, (based on physical examination, radiography, and 5 times the recommended dosage for 6 months.
electrocardiography, and clinical pathology).
See Table 3 for cardiac pathology results. The cardiac Attitude, pleural effusion, coughing, activity level, pathology/histopathology noted in the 3X and 5X furosemide dosage change, cardiac size, body dose groups is typical of positive inotropic and weight, survival, and owner observations were vasodilator drug toxicity in normal dog hearts, secondary evaluations contributing information and is associated with exaggerated hemodynamic supportive to product effectiveness and safety.
responses to these drugs. None of the dogs developed Based on protocol compliance and individual signs of heart failure and there was no mortality.
case integrity, 265 cases (134 Vetmedin, 131 active Table 3: Incidence of Cardiac Pathology/
control) were evaluated for treatment success Histopathology in the Six-month Safety Study
on Day 29. See Table 2 for effectiveness results.
Table 2: Effectiveness Results for the 56-Day
Severe left ventricular hypertrophy with
One 3X and
multifocal subendocardial ischemic lesions
two 5X dogsa
Moderate to marked myxomatous
Three 5X dogs
Active Control Group
thickening of the mitral valves
Myxomatous thickening of the
One 3X and
two 5X dogs
Endocardial thickening of the left
One 1X, two 3X,
ventricular outflow tract
and two 5X dogs
Left atrial endocardial thickening (jet
One 3X and
lesions) in 2 of the dogs that developed
one 5X dog
murmurs of mitral valve insufficiency
Granulomatous inflammatory lesion in the
One 3X dog
right atrial myocardium
a Most of the gross and histopathologic findings occurred in these 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 Boehringer Ingelheim Vetmedica, Inc.
Vetmedin at the label dose (1X). Mean diastolic blood pressure was decreased in the 3X group (82 mmHg). Mean systolic blood pressure was decreased in the 5X group (117 mmHg) compared licensed to Boehringer Ingelheim Vetmedica, Inc.
to the control group (124 mmHg). None of thedogs had clinical signs of hypotension.
2008 Boehringer Ingelheim Vetmedica, Inc.
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 groupshad slightly higher numbers of isolated ventricularectopic complexes (VEs). The maximum numberof non-escape VEs recorded either at baselineor in a control group dog was 4 VEs/24 hours.
At either Week 4 or Week 20, three 3X group dogshad maximums of 33, 13, and 10 VEs/24 hours,and two 5X group dogs had maximums of 22 and9 VEs/24 hours. One 1X group dog with no VEs atbaseline had 6 VEs/24 hours at Week 4 and againat Week 20. Second-degree atrioventricular heartblock was recorded in one 3X group dog at Weeks4 and 20, and in one dog from each of the 1Xand 5X groups at Week 20. None of the dogshad clinical signs associated with theseelectrocardiogram changes.
Treatment was associated with small differencesin mean platelet counts (decreased in the 3X and1X 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 valuesfor these variables were within the normal range.
Three 1X and one 5X group dogs had mild elevationsof alkaline phosphatase (less than two timesnormal). Loose stools and vomiting wereinfrequent and self-limiting.
Storage Information: Store at controlled room
temperature 59-86°F (15-30°C).
Vetmedin® (pimobendan) Chewable Tablets:
Available as 1.25 or 5 mg oblong half-scored
chewable tablets — 50 tablets per bottle.
ORTHOPAEDIC INFECTIONS Condition Useful information First line Second line Duration EITHER Teicoplanin ω IV Acute Septic Benzylpenicillin IV Arthritis PLUS Flucloxacillin IV 800mg) 12hourly for 3 Osteomyelitis PLUS EITHER Sodium OR Doxycycline PO fusidateΩ tablets PO OR RifampicinΩ PO PLUS EITHER Sodium fusidateΩ tablets PO