Amodip Flavoured Tablets (Canada)

Company: Ceva Animal Health

Amlodipine Besilate Tablets, Mfr. Std.

1.25 mg amlodipine

Veterinary Use Only

DIN 02497492

Description

Each tablet contains 1.73 mg of Amlodipine besilate (equivalent to 1.25 mg of amlodipine). The palatable tablets are scored and oblong in shape. The tablets can be divided into two equal parts.

Therapeutic classification:

Anti-hypertensive agent

Indication:

Amodip is indicated for the reduction of systolic blood pressure in cats with systemic hypertension.

Dosage and Administration

Amlodipine tablets should be administered orally with or without food at a dose of 0.125 - 0.25 mg/kg once daily.

If starting at the lower dose of 0.125 mg/kg, the dose may be doubled up to 0.25 mg/kg once daily if adequate clinical response has not been achieved (e.g. systolic blood pressure remaining over 150 mmHg or a decrease of less than 15% from the pre-treatment measurement) after 14 days of treatment. After 1 month of treatment, if adequate response has not been achieved, the treatment plan should be re-assessed.

Tablets can be broken in half to accurately dose the cat.

Contraindications

- Do not use in the case of cardiogenic shock and severe aortic stenosis.

- Do not use in cases of hepatic failure.

- Do not use in cases of known hypersensitivity to the drug.

Cautions:

The primary cause and/or co-morbidities of systemic hypertension, such as hyperthyroidism, chronic kidney disease and diabetes, should be identified and treated.

Systemic hypertension should be confirmed by measurement of systolic blood pressure before commencing therapy.

Systolic blood pressure should be routinely measured during treatment with administration of the drug over an extended period of time.

Administration of amlodipine may sometimes result in a decrease in serum potassium and chloride levels. Monitoring of those levels is recommended during treatment. Older cats with hypertension and chronic kidney disease (CKD) may also suffer from hypokalaemia as a result of their underlying disease.

Amlodipine is metabolised by the liver. As no studies have been conducted in cats with liver disease, safe use of the drug in these animals has not been established.

Safety has not been evaluated in cats with congestive heart failure.

The safety of amlodipine has not been established in breeding, pregnant or lactating cats.

In laboratory rodent studies there was no evidence of teratogenicity.

Concomitant use of amlodipine with other drugs that may reduce blood pressure may cause hypotension. These drugs include: diuretics, beta-blockers, other calcium channel blockers, inhibitors of the renin angiotensin aldosterone system (renin inhibitors, angiotensin II receptor blockers, angiotensin converting enzyme inhibitors (ACEi), and aldosterone antagonists), other vasodilators and alpha-2 agonists. Blood pressure should be closely monitored when administering amlodipine with these drugs and to ensure the cat is adequately hydrated.

Concomitant use of amlodipine with negative chronotropes and inotropes (such as beta-blockers, cardioselective calcium channel blockers and antifungal azoles (e.g. itraconazole)) may reduce force and rate of contraction of the heart muscle. Particular attention must be paid before administering amlodipine with these drugs in cats with ventricular dysfunction.

Warnings

Keep out of reach of children. In case of accidental oral ingestion, seek medical advice.

Adverse Reactions

Although all adverse reactions are not reported, the following information is based on voluntary post-approval drug experience reporting. It is generally recognized that this results in significant under-reporting. The adverse events listed here reflect reporting and not necessarily causality.

Adverse events are listed by body system, in decreasing order of frequency:

- Digestive tract disorders: Emesis, gingival disorder (hyperplasia)

- Systemic disorders: Anorexia, lethargy, lack of efficacy, dehydration, weight loss

If you notice any serious effects or other effects not mentioned in this package leaflet, please inform your veterinarian.

Overdose:

Hypotension may occur in cases of accidental overdose. Therapy is symptomatic.

Clinical Pharmacology

Pharmacodynamics:

Amlodipine is a voltage dependent calcium channel blocker, member of the dihydropyridine group, binding selectively to the L-type of channels found in vascular smooth muscle, cardiac muscle and cardiac nodal tissue.

The major blood pressure lowering effect of amlodipine is related to its dilatory action on arteries and arterioles, while amlodipine has little effect on the venous circulation.

In cats with hypertension, once daily dosing with amlodipine tablets provided clinically significant reductions in systolic blood pressure and due to the slow onset of action of amlodipine, acute hypotension and reflex tachycardia tend not to occur.

Pharmacokinetics:

Absorption:

After a single oral administration of 0.25 mg/kg, amlodipine was well absorbed with peak plasma levels between 3 to 6 hours post dose. The absolute bioavailability was estimated to be 74% and the peak plasma level was 23 ng/ml, in fasted state.

Distribution:

Amlodipine is highly bound to plasma proteins. In vitro protein binding in cat plasma is 97%. The volume of distribution is 9.6 l/kg.

Biotransformation:

Amlodipine is metabolised by the liver in laboratory animals and humans. All known metabolites lack pharmacological activity. All amlodipine metabolites found in vitro in cat hepatocytes have been earlier identified in incubations of rat, dog and human hepatocytes.

Elimination:

The mean plasma elimination half-life of amlodipine is 53 hours in healthy cats. At 0.125 mg/kg/day, plasma level of amlodipine was approaching steady-state by 2 weeks in healthy cats. Total plasma clearance in healthy cats is estimated to be 2.3 ml/min/kg.

Excretion balance has been characterised in humans and several animal species, but not in the cat. In dogs, equal distribution of radioactivity was found in the urine and faeces.

Safety:

In the target animal safety study, four groups of 8 (4 male and 4 female) healthy adult cats were orally administered amlodipine tablets at doses of 0, 0.25, 0.75 and 1.25 mg/kg per day for 6 months. In normotensive cats amlodipine did not produce substantial blood pressure changes. After approximately 12 weeks of treatment hyperplastic gingivitis was observed in the amlodipine treated cats. The incidence and severity was dose and time related. Cats in the 0.25 mg/kg/day group had reactive mandibular lymph nodes hyperplasia, and increased Leydig cell vacuolisation and hyperplasia. Cats in the 0.75 mg/kg and 1.25 mg/kg groups had moderate to very severe hyperplastic gingivitis. Cats in the 0.75 and 1.25 mg/kg groups had decreased plasma potassium and chloride values and an increase in urinary volume associated with decreased urinary specific gravity was observed. One male cat in the 1.25 mg/kg group had an esophageal erosion with a moderate lymphogranulocytic inflammation from treatment with the tablets or stress-related gastro-esophageal reflux.

In a two-week tolerance study of 4 healthy cats, doses between 1.75 mg/kg and 2.5 mg/kg were administered, and mortality in 1 cat and severe morbidity in 1 cat occurred.

In the European clinical efficacy study 77 cats received amlodipine treatment for 3 months and were evaluated for safety.

Summary of Adverse Events during amlodipine treatment in the Clinical Field Study n=77

During the clinical efficacy study, a 16 year old, male neutered cat with hyperthyroidism died suddenly, one day after starting treatment with amlodipine. The causal relationship of the drug to this fatal adverse event was assessed as possible by the Safety Officer but as unlikely by the investigator.

Efficacy:

In a multi-centered, European clinical study, 77 client-owned cats with persistent systolic blood pressure (SBP) >165 mmHg were randomised to receive amlodipine (n=42 cats) at an initial target dose of 0.125 (range 0.125 - 0.25 mg/kg) or placebo tablets (n=35 cats), once daily. If response was not satisfactory after 14 days, the dose may have been doubled up to 0.25 - 0.5 mg/kg. SBP was measured after 14 and 28 days and on study day 28 treatment was considered successful if SBP was reduced by 15% or more of pre-treatment SBP or to below 150 mmHg. 25 out of 40 cats (62.5%) given amlodipine were successfully treated compared with 6 out of 34 (17.6%) given placebo, amlodipine decreased SBP statistically significantly (p < 0.001). The Odds Ratio was 7.9 with a 95% confidence interval 2.6 - 24.01. Of the 40 amlodipine treated cats, 16 (40%) of the cats had their systolic blood pressure reduced to less than 150 mmHg and 18 (45%) of the cats had a 15% reduction or more of their SBP. In the placebo group, only 6 cats (17.6%) had their systolic blood pressure reduced to less than 150 mmHg and a 15% reduction or more of their SBP.

During the clinical study, concomitant use of medication to treat a primary disease associated with increased systolic blood pressure, such as hyperthyroidism, and chronic kidney disease associated with proteinuria, was allowed as long as the primary disease was stable with no new medications or dose adjustment of the current medication. The palatability of Amodip^® was also assessed during the first 4 weeks; 80% of the cats took the tablets voluntarily (62.5% with palatable food and 17.5% without food), while 20% of the cats had to be pilled.

Storage

Store between 15 and 25°C. Protect from light. Shelf life of halved tablets: 24 hours.

Any half tablets remaining after 24 hours should be discarded.

Presentation:

Amodip^® Flavoured Tablets are available in the following package sizes:

3 blisters of 10 tablets (30 tablets) or 10 blisters of 10 tablets (100 tablets).

Ceva Animal Health Inc.,150 Research Lane, Suite 225, Guelph, ON N1G 4T2

1-800-510-8864

Amodip^® is a registered trademark of Ceva Santé Animale, France

F4545-3120201

S1569-02-S1571-02-0322

CPN: 1221151.1