1. NAME OF THE VETERINARY MEDICINAL PRODUCT

FORTEKOR PLUS 1.25 mg/2.5 mg tablets for dogs FORTEKOR PLUS 5 mg/10 mg tablets for dogs

 

1. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains:

Active substances:

	Pimobendan	Benazepril
		hydrochloride
FORTEKOR PLUS 1.25 mg/2.5 mg tablets	1.25 mg	2.5 mg
FORTEKOR PLUS 5 mg/10 mg tablets	5 mg	10 mg
Excipients:
	Brown oxide
	iron E172
FORTEKOR PLUS 1.25 mg/2.5 mg tablets	0.5 mg
FORTEKOR PLUS 5 mg/10 mg tablets	2mg

 

For the full list of excipients, see section 6.1.

 

1. PHARMACEUTICAL FORM

Oval, bilayer tablets, white and light brown, with a score line on both sides.

The tablets can be divided into equal halves.

 

1. CLINICAL PARTICULARS

4.1      Target species

Dogs.

4.2      Indications for use, specifying the target species

For the treatment of congestive heart failure due to atrioventricular valve insufficiency or dilated cardiomyopathy in dogs. FORTEKOR PLUS is a fixed-dose combination and should only be used in subjects whose clinical signs are successfully treated by simultaneous administration of the same doses of the individual components (pimobendan and benazepril hydrochloride).

4.3      Contraindications

It is not used in case of hypertrophic cardiomyopathies or clinical conditions in which increasing the heart rate is not possible for functional or anatomical reasons (e.g. aortic or pulmonary stenosis).

Do not use in case of hypotension, hypovolemia, hyponatremia or acute renal failure.

Do not use during pregnancy and lactation (see section 4.7).

Do not use in case of hypersensitivity to the active substances or any of the excipients.

4.4 Special warnings for each target species

It doesn't exist.

 

4.5 Special precautions for use

In the case of chronic kidney disease, it is recommended to check the dog's hydration status before starting therapy and to monitor plasma creatinine and the number of erythrocytes in the blood during therapy.

 

As pimobendan is metabolised in the liver, the product should not be administered to dogs suffering from severe hepatic impairment.

 

The efficacy and safety of the product have not been established in dogs weighing less than 2.5 kg or under 4 months of age.

 

Special precautions to be taken by the person administering the veterinary medicinal product to animals

 

Wash your hands after use.

 

People with known hypersensitivity to pimobendan or benazepril hydrochloride should avoid contact with the veterinary medicinal product.

 

In case of accidental oral ingestion, seek medical advice immediately and show the package leaflet or the label to the physician.

 

Pregnant women should take special care to avoid accidental oral exposure, as angiotensin-converting enzyme (ACE) inhibitors have been shown to affect the fetus during human pregnancy.

 

4.6 Adverse reactions (frequency and seriousness)

Pimobendan

In rare cases, a moderate positive chronotropic effect and vomiting may occur. These effects are, however, dose-dependent and can be avoided by reducing the dose in such situations.

In rare cases, transient diarrhea, anorexia or lethargy have been observed.

 

Benazepril hydrochloride

A small number of dogs may experience transient vomiting, incoordination, or signs of fatigue. In dogs with chronic kidney disease, benazepril may increase plasma creatinine levels at the beginning of therapy. The modest increase in plasma creatinine levels following administration of ACE inhibitors is consistent with the reduction in glomerular hypertension induced by these agents, so there is no reason to stop treatment in the absence of other signs.

 

The frequency of adverse reactions is defined using the following convention:

- very common (more than 1 in 10 animals showing adverse reactions during a treatment)

- common (more than 1 but less than 10 animals in 100 animals)

- uncommon (more than 1 but less than 10 animals in 1,000 animals)

- rare (more than 1 but less than 10 animals in 10,000 animals)

- very rare (less than 1 animal in 10,000 animals, including isolated reports)

 

 

4.7 Use during pregnancy or lactation Do not use during pregnancy or lactation.

The safety of FORTEKOR PLUS has not been tested in dogs during breeding, gestation or lactation.

Laboratory studies in rats and rabbits with pimobendan have shown fetotoxic effects at maternally toxic doses. Laboratory studies in rats and rabbits with pimobendan have shown no effect on fertility. Laboratory studies in rats have shown that pimobendan is excreted in milk.

Laboratory studies in rats with benazepril have shown fetotoxic effects (fetal urinary tract malformation) at maternally non-toxic doses. It is not known whether benazepril is secreted in the milk of lactating bitches.

 

4.8 Interaction with other medicinal products and other forms of interaction

In dogs with congestive heart failure, benazepril hydrochloride and pimobendan have been administered in combination with digoxin and diuretics without demonstrable adverse interactions.

In pharmacological studies, no interaction was detected between the cardiac glycoside ouabain and pimobendan. The increase in cardiac contractility induced by pimobendan is attenuated in the presence of the calcium antagonist verapamil and the β-antagonist propranolol.

In humans, the combination of angiotensin converting enzyme (ACE) inhibitors and non-steroidal anti-inflammatory drugs (NSAIDs) may lead to reduced antihypertensive efficacy or renal impairment. Therefore, the concomitant use of FORTEKOR PLUS with NSAIDs or any other drug with a hypotensive effect should be carefully considered before using such combinations.

The combination of FORTEKOR PLUS and other antihypertensive agents (e.g. calcium channel blockers, β-blockers or diuretics), anaesthetics or sedatives may lead to additive hypotensive effects. Renal function and signs of hypotension (lethargy, weakness, etc.) should be closely monitored and treated as necessary.

Interactions with potassium-sparing diuretics such as spironolactone, triamterene or amiloride cannot be excluded. Therefore, monitoring of plasma potassium levels is recommended when FORTEKOR PLUS is used in combination with potassium-sparing diuretics due to hyperkalemia.

 

4.9 Amounts to be administered and route of administration

Oral administration.

Dosage and treatment regimen

 

FORTEKOR PLUS is a fixed combination product that should only be used in dogs that require both active substances to be administered concomitantly at this fixed dose.

The recommended dose range for FORTEKOR PLUS is 0.25 - 0.5 mg pimobendan per kg body weight and 0.5 - 1 mg benazepril hydrochloride per kg body weight divided into two daily doses. FORTEKOR PLUS tablets should be administered orally, twice daily, 12 hours apart (morning and evening) and approximately 1 hour before feeding.

The tablets can be broken along the midline.

The table below can be used for guidance.

Weight	Strength and number of tablets to be administered
	FORTEKOR PLUS 1.25 mg/2.5 mg			FORTEKOR PLUS 5 mg/10 mg
dog (kg)	tablet			tablet
	Morning		Evening	Morning		Evening
2.5 - 5	0.5		0.5
5 - 10	1		1
10 - 20				0.5		0.5
20 - 40				1		1
Over 40 kg				2		2

 

4.10 Overdose (symptoms, emergency procedures, antidotes), as appropriate

In case of overdose, the dog should be treated symptomatically. Transient reversible hypotension may occur in case of accidental overdose. Therapy will consist of intravenous infusion (IV) of warm isotonic saline as required.

 

4.11 Waiting time

That's not the case.

5.1 Pharmacodynamic properties

Benazepril hydrochloride is a prodrug that is hydrolyzed in vivo to its active metabolite, benazeprilat. Benazeprilat is a highly potent and selective ACE inhibitor, preventing the conversion of inactive angiotensin I to active angiotensin II, thereby reducing aldosterone synthesis. Benazepril therefore blocks the effects mediated by angiotensin II and aldosterone, including vasoconstriction of arteries and veins, sodium and water retention by the kidneys, and remodeling effects (including pathological cardiac hypertrophy and degenerative renal changes).

In dogs with congestive renal failure, benazepril hydrochloride reduces blood pressure and volume load on the heart. Benazepril prolonged the time to worsening heart failure and death, improved clinical status, reduced coughing, and improved exercise tolerance in dogs with symptomatic congestive heart failure caused by valvular disease or dilated cardiomyopathy.

Pimobendan, a benzimidazole-pyridazinone derivative, is a non-sympathomimetic, non-glycoside, inotropic agent with effective vasodilator properties. It increases the calcium sensitivity of cardiac myofilaments and inhibits phosphodiesterase (type III). It also exhibits vasodilator action by inhibiting the activity of phosphodiesterase type III.

5.2 Pharmacokinetic particularities

Absorption

After oral administration of pimobendan alone, the absolute bioavailability of the active ingredient is 60-63%. As this bioavailability is considerably reduced when pimobendan is administered with food or shortly thereafter, it is recommended to treat animals approximately 1 hour before feeding.

Following oral administration of benazepril hydrochloride alone, systemic bioavailability is incomplete (~13%) in dogs due to incomplete absorption (38%) and first-pass metabolism. Benazepril levels decline rapidly as the drug is partially metabolized to benazeprilat by hepatic enzymes. There is no significant difference in the pharmacokinetics of benazeprilat when benazepril hydrochloride is administered to fed or fasted dogs.

Following oral administration of FORTEKOR PLUS tablets at twice the recommended dose in dogs, peak levels of both components are reached rapidly (Tmax 0.5 hours for benazepril hydrochloride and 0.85 hours for pimobendan), with peak concentrations (Cmax) for benazepril hydrochloride of 35.1 ng/ml and 16.5 ng/ml for pimobendan. Peak levels of benazeprilat were observed after 1.9 hours with peak concentrations (Cmax) of 43.4 ng/ml.

Distribution

The steady-state volume of distribution is 2.6 l/kg after intravenous administration of pimobendan alone, indicating that pimobendan has already distributed into tissues. The mean in vitro plasma protein binding is 93%.

Benazeprilat concentrations decline in a biphasic manner: the initial, rapid phase (t1/2 = 1.7 hours) represents the elimination of free drug, while the terminal phase (t1/2 = 19 hours) reflects the release of benazeprilat that has been bound to ACE, primarily from tissues. Benazepril and benazeprilat are extensively bound to plasma proteins (85-90%), and in tissues they are found primarily in the lungs, liver, and kidneys.

Repeated administration of benazepril hydrochloride leads to a slight bioaccumulation of benazeprilat (R = 1.47), with steady state being achieved within a few days (4 days).

Metabolism

Pimobendan is oxidatively demethylated to its main metabolite, O-desmethyl pimobendan.

The next metabolic pathways are phase II, glucuronides and sulfates.

Benazepril hydrochloride is partially metabolized by liver enzymes to the active metabolite benazeprilat.

Elimination

The elimination half-life of pimobendan dosed with FORTEKOR PLUS tablets is 0.5 hours, consistent with the high clearance of the compound. The major active metabolite of pimobendan is eliminated with a half-life of 2.6 hours. Pimobendan is excreted primarily in the feces and, to a lesser extent, in the urine.

The elimination half-lives of benazepril hydrochloride and benazeprilat, when dosed with FORTEKOR PLUS tablets, are 0.36 hours and 8.36 hours, respectively. Benazeprilat is excreted via the biliary (54%) and urinary (46%) routes in dogs. Benazeprilat clearance is not affected in dogs with impaired renal function; therefore, no dosage adjustment of FORTEKOR PLUS is necessary in dogs with renal impairment.

 

6.2 Incompatibilities

That's not the case.

6.3 Shelf life

Shelf life of the veterinary medicinal product as packaged for sale: 18 months

Any remaining half tablets should be discarded after 1 day.

 

6.4 Special precautions for storage

 

Store below 25°C.

Keep the blister in the outer carton in order to protect from moisture.

Any remaining half tablet should be placed back in the opened blister and kept (for no more than 1 day) in the original carton, out of the sight and reach of children.

 

6.5 Nature and composition of primary packaging

Tablets of both strengths are packaged in aluminum/aluminum blisters placed in an outer cardboard box.

1.25 mg/2.5 mg tablets: pack size of 30 

5 mg/10 mg tablets: pack size of 30