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KELAPRIL 2.5 mg / 5 mg / 20 mg ORAL TABLETS FOR DOGS AND CATS One tablet contains 2.5 mg, 5 mg or 20 mg benazepril hydrochloride easy Film-coated tablets for administration well Treats cardiac (dogs) as ency as renal (cats) insuffici Very well tolerated KELAPRIL 2.5 mg / 5 mg / 20 mg film coated tablets for dogs and cats Inhibitors of the angiotensin converting enzyme (ACE) are of great benefit for the management of congestive heart failure in dogs, improving symptoms and tolerance to exercise as well as extending the life span of the animal. In cats with chronic renal insufficiency they decrease proteinuria and systemic arterial pressure, and delay the progression of the disease. The Renin-Angiotensin-System Congestive heart failure in dogs The precursor molecule Angiotensinogen is produced in the liver and cleaved to make Angiotensin I by rennin, an enzyme released by the juxtaglomerular cells. This Angiotensin I is in turn converted into Angiotensin II catalysed by the Angiotensin Converting Enzyme or ACE, located in the pulmonary and renal endothelium. In congestive heart failure the heart is unable to provide adequate circulation to meet the body’s needs. Chronic valvular disease in small dog breeds, and dilated cardiomyopathy are the most common causes. Benazepril blocks the conversion of Angiotensin I into Angiotensin II, and inhibits in this way its rapid response, slow response, as well as morphologic reactions. Due to increased pressure in the veins, fluid leaks into the lungs (pulmonary edema) and the peritoneal cavity (ascites). Early signs are non-specific, but when failure progresses rapid breathing, coughing, abdominal swelling and a marked loss of weight become apparent. At a later stage laboured breathing, cyanosis and syncope occur. Clinical efficacy 162 dogs with congestive heart failure 1 were treated with 0.25 – 0.5 mg benazepril per kg bw. Benazepril significantly extended the life span of the dogs from 158 in the placebo group, to 428 days in the treated group. ACE inhibition Benazepril acts by inhibition of the Angiotensin Converting Enzyme, resulting in less conversion of Angiotensin I into Angiotensin II. Benazepril will therefore lead to vasodilatation and a decrease in fluid retention. As a consequence the blood flows more freely through the widened vessels, thereby reducing the amount of work the heart has to do. Pharmacokinetics After oral administration benazepril is rapidly absorbed from the gastrointestinal tract and consequently hydrolyzed in the liver to form the active moiety benazeprilat. Following the administration of KELAPRIL maximal serum concentrations are reached after 1.43 hr (Tmax) in dogs and 1.91 hr in cats. After a period of one year, 49 % of the benazepril treated dogs survived, compared to only 20 % in the placebo group. Results also indicate that the outcome is significantly better when benazepril therapy starts early in the progress of the disease. Benazepril delayed the time to evolve from moderate (class II) to advanced (class III) cardiac insufficiency by a factor of 2 compared to placebo: 394 days instead of 209 days. At 28 days after the start of treatment significantly more dogs showed improved exercise tolerance (57 %) and global condition (61 %) as compared to placebo treated animals (34 % and 33 % resp.). Tolerance in dogs The percentage of dogs showing undesirable events was not significantly different between the benazepril group and the placebo group. Chronic renal insufficiency in cats Chronic renal failure is characterized by gradual and irreversible decrease of glomerular filtration rate, result of a gradual loss of renal functional mass2. In compensation the remaining nephrons suffer functional and structural changes in order to maintain filtration rate constant. These functional adaptations refer to hyperfiltration, which is produced by an increase in glomerular capillaries blood flow and pressure. This increased glomerular pressure is in the long run deleterious for the kidney. It leads to proteinuria and consecutive local inflammation causing progressive renal injury. Benazepril may lower glomerular pressure by decreasing systemic blood pressure and vasoconstriction of the efferent arterioles. In cats the Urine Protein / Creatinine (UPC) ratio of ≥ 0.5 is indicative of persistent renal proteinuria. In animals with naturally occurring Chronic Renal Faillure and an UPC > 1.0, significantly longer survival times were evident: 402 days in benazepril group vs. 149 days in placebo group. Beneficial effect on appetite was observed in cats with more pronounced proteinuria (UPC >1.0). Tolerance in cats Benazepril is safe in cats with chronic renal failure, because the active moiety, benazeprilat, is principally (85 %) eliminated via biliary excretion, and therefore does not accumulate in the body of animals with renal diseases. Posology KELAPRIL should be given orally once daily, with or without food. The duration of treatment is unlimited. Dogs A minimum dose of 0.25 mg (range 0.25-0.5) benazepril HCl per kg body weight once daily. The dose may be doubled, still administered once daily, to a minimum dose of 0.5 mg/kg (range 0.5-1.0), if judged clinically necessary and advised by the veterinary surgeon. KELAPRIL 2.5 mg Weight of Double Standard dog (kg) dose dose 2.5 - 5 0.5 tablet > 5 - 10 1 tablet > 10 - 20 – 1 tablet KELAPRIL 5 mg Standard dose – Standard dose Double dose – 2 tablets 0.5 tablet 1 tablet KELAPRIL 20 mg Double dose – – – 1 tablet – – 2 tablets – – > 20 - 40 – – – – 0.5 tablet 1 tablet > 40 - 80 – – – – 1 tablet 2 tablets Cats KELAPRIL 2.5 mg and 5 mg should be administered orally at a minimum dose of 0.5 mg (range 0.5-1.0) benazepril HCl per kg body weight once daily according to the following table: Weight of cat (kg) KELAPRIL 2.5 mg KELAPRIL 5 mg 2.5 - 5 1 tablet 0.5 tablet > 5 - 10 2 tablets 1 tablet References 1.The BENCH STUDY GROUP The effect of benazepril on survival times and clinical signs in dogs with congestive heart failure: Results of a multicenter, prospective, rando-mized, double-blinded, placebo-controlled, long-term clinical trial. Journal of Veterinary Cardiology, Vol. 1, No. 1, May 1999. 2. KING J.N., GUNN-MOORE D.A., TASKER S., GLEADHILL A., STREHLAU G., BENRIC STUDY GROUP. Tolerability and efficacy of Benazepril in cats with chronic kidney di-sease. J. Vet. Intern. Med. 20:1054-1064 – 2006. PRIL Advantages of KELA d cats § efficacious in dogs an as well § treats cardiac (dogs) ncy as renal (cats) insufficie § very well tolerated FOR ANIMAL TREATMENT ONLY RESTRICTED VETERINARY MEDICINE KELAPRIL 2.5 mg, film-coated tablets for dogs and cats KELAPRIL 5 mg, film-coated tablets for dogs and cats KELAPRIL 20 mg, film-coated tablets for dogs Benazepril hydrochloride ACTIVE INGREDIENT AND QUANTITIES: KELAPRIL 2.5 mg: Each tablet contains 2.5 mg Benazepril hydrochloride. KELAPRIL 5 mg: Each tablet contains 5 mg Benazepril hydrochloride. KELAPRIL 20 mg: Each tablet contains 20 mg Benazepril hydrochloride. USE CLAIMS: KELAPRIL 2.5 mg / KELAPRIL 5 mg: For the treatment of heart failure due to mitral regurgitation and dilated cardiomyopathy in dogs, hypertrophic cardiomyopathy in cats, and chronic renal insufficiency in dogs and cats. KELAPRIL 20 mg: For the treatment of heart failure due to mitral regurgitation and dilated cardiomyopathy and chronic renal insufficiency in dogs. DIRECTIONS FOR USE: For oral use only. KELAPRIL should be given once daily, with or without food. The duration of treatment is unlimited. DOGS: In dogs, the recommended oral dose is 0.25-0.5mg benazepril hydrochloride/kg body weight, given according to the following regime: KELAPRIL 2.5 mg Weight of Standard dog (kg) dose Double dose 2.5 - < 5 0.5 tablet 1 tablet 5 - 10 1 tablet KELAPRIL 5 mg Standard dose 2 tablets 0.5 tablet 11 - 20 1 tablet Double dose KELAPRIL 20 mg Standard dose Double dose 1 tablet 2 tablets 21 - 40 0.5 tablet 1 tablet 41 - 80 1 tablet 2 tablets The dose may be doubled, still administered once daily, if judged clinically necessary and advised by the veterinary surgeon. CATS: In cats, KELAPRIL should be administered orally at a dose of 0.5-1.0 mg benazepril hydrochloride/kg body weight once daily according to the following table: Weight of cat (kg) KELAPRIL 2.5 mg KELAPRIL 5 mg 2.5 - 5 1 tablet 0.5 tablet > 5 - 10 2 tablets 1 tablet REGISTRANT/NEW ZEALAND AGENT: Registered to KELA N.V., St. Lenaartseweg 48, 2320 Hoogstraten, BELGIUM, [email protected], + 32 3 340 04 11, manufactured in Belgium. New Zealand agent: Phoenix Pharm Distributors Ltd, [email protected], + 9 476 7391. EXPIRY DATE: Tablet halves should be used within 2 days. Shelf-life of the veterinary medicinal product as packaged for sale: 24 months. NET CONTENTS: 28 tablets – 98 tablets. STORAGE INSTRUCTIONS: KELAPRIL 2.5 mg: Store below 25°C in original blister. KELAPRIL 5 mg: Store below 30°C in original blister. KELAPRIL 20 mg: Store below 30°C in original blister. Keep out of the reach and sight of children. Store in a dry place. Each time an unused half tablet is stored, it should be returned to the open blister space and inserted back into the cardboard box. ADVERSE EFFECTS, CAUTIONS AND CONTRAINDICATIONS: Adverse effects: On rare occasions transient signs of hypotension, such as lethargy and ataxia may occur. In cats with chronic renal insufficiency, KELAPRIL may increase plasma creatinin concentrations at the start of therapy. This effect is related to the therapeutic effect of the product in reducing blood pressure, and therefore is not necessarily a reason to stop therapy in the absence of other signs. As is routine in cases of chronic renal insufficiency, it is recommended to monitor plasma creatinine during therapy. Benazepril reduced erythrocyte counts in normal cats at high doses, but this effect was not observed at the recommended dose during clinical trials in cats with chronic renal insufficiency. As is routine in cases of chronic renal insufficiency, it is recommended to monitor erythrocyte counts during therapy. KELAPRIL may increase food consumption and body weight in cats. Emesis, anorexia, dehydration and lethargy have been reported in rare occasions in this species. If you notice any serious effects or other effects not mentioned in this leaflet, please inform your veterinary surgeon. Special warnings for each target species: The efficacy and safety of the product has not been established in dogs and cats below 2.5 kg body weight. Special precautions for use in animals: No evidence of renal toxicity to the product has been observed in dogs or cats during clinical trials. As is routine in cases of renal insufficiency, it is recommended to monitor plasma creatinin and urea during therapy. User warnings: Wash hand after use. Pregnant women should take special care to avoid accidental oral exposure. People sensitive to benazepril hydrochloride or some of the excipients should not handle this product. In case of accidental ingestion, seek medical advice immediately and show this label to the doctor. Use during pregnancy and lactation: The safety of KELAPRIL has not been tested in breeding, pregnant or lactating dogs or cats. The product should therefore be used only if justified clinically, considering the risk/benefit ratio. ACE inhibitors have been found to be teratogenic in the second and third trimesters in other species. Interaction with other medicinal products and other forms of interaction: None known in dogs or cats. In dogs with heart failure, benazepril has been given in combination with digoxin, diuretics and anti-arrhythmic drugs without demonstrable adverse interactions. The combination of KELAPRIL and other anti-hypertensive agents, anaesthetics or sedatives may lead to additive hypotensive effects. Therefore, concurrent use of other medications with a hypotensive effect should be considered with care. Renal function and signs of hypotension (lethargy, weakness etc) should be monitored closely and treated when necessary. Interactions with potassium preserving diuretics like spironolactone, triamterene or amiloride cannot be ruled out. It is recommended to monitor plasma potassium levels when using benazepril in combination with a potassium sparing diuretic as life threatening reactions are possible. Overdose (symptoms, emergency procedures, antidotes): KELAPRIL is well tolerated in the target species. In normal dogs, overdosage up to 200-fold was asymptomatic. In normal cats, a 10-fold overdosage daily for one year was asymptomatic. Transient reversible hypotension may occur in cases of accidental overdosage. Therapy should consist of intravenous infusion of warm isotonic saline. Special precautions for the disposal of unused product or waste materials: Any unused product or waste material should be disposed of in accordance with local requirements. Contraindications: Do not use in case of hypersensitivity to the active substance or to any of the excipients. Do not use in cases of hypotension, hypovolaemia, hyponatraemia or acute renal failure. Do not use in cases of cardiac output failure due to aortic or pulmonary stenosis. Do not use in pregnant or lactating dogs or cats because the safety of benazepril hydrochloride has not been established during pregnancy or lactation in these species. KELAPRIL 2.5 mg: ACVM Registration No. A10942 KELAPRIL 5 mg: ACVM Registration No. A10943 KELAPRIL 20 mg: ACVM Registration No. A10944 See www.foodsafety.govt.nz for registration conditions. PHOENIX PHARM DISTRIBUTORS LTD § PO Box 31-363, Milford, Auckland Telephone: 09 476 7391 § Facsimile: 09 479 5555 E-mail: [email protected] § Website: www.phoenixpharm.co.nz