I. introduction - Veterinary Medicines Directorate

Product Name: Vetmedin 5.0mg Flavour Tablets
MA Holder: Boehringer Ingelheim Ltd
The product Vetmedin 5.0 mg has been authorised as a Line Extension to the Marketing
Authorisation for Vetmedin 5.0 mg Capsules to change to a new pharmaceutical form, a
chewable tablet. The application is submitted in accordance with Article 12(3) of Directive
2001/82/EC (as amended by 2004/28/EC).
This product contains the known active substance, pimobendan. The target species is the dog.
The indication is for the treatment of canine congestive heart failure originating from valvular
insufficiency (mitral and/or tricuspid regurgitation) or dilated cardiomyopathy.
The product is produced and controlled using validated methods and tests which ensure the
consistency of the product released on the market. It has been shown that the product can be
safely used in the target species; the slight reactions observed are indicated in the SPC. The
applicant justifies the new pharmaceutical form because of the increasing trend for palatable
oral pharmaceutical forms for companion animals.
The product is safe for the user, and for the environment, when used as recommended.
Suitable warnings and precautions are indicated in the SPC. The efficacy of the product was
demonstrated according to the claims made in the SPC. The overall risk/benefit analysis is in
favour of granting a marketing authorisation.
Product Development and Composition
The product contains pimobendan and excipients citric acid, maize starch, lactose, povidone,
croscarmellose sodium, artificial powdered beef flavour, silica, colloidal and magnesium
Tablets are elongated, scored and mottled brown in colour, with fine white spots. Both upper
and lower faces are scored and imprinted. To the left of each score, Vetmedin 5.0 mg is
imprinted P03. To the right of the score each tablet is imprinted with the Boehringer Ingelheim
logo. The 5.0 mg tablet is 24.7 mm long, 14.0 mg wide and approximately 6.1 mm thick.
A single pack size is comprised of 50 tablets in a white, high density polyethylene bottle with a
white, polypropylene, child-resistant closure. Stability data demonstrate that no advantage is
gained by the inclusion of an induction seal or a desiccant or by packaging tablets individually in
aluminium foil or PVC blister packs. The particulars of the containers and controls performed
are provided and conform to the regulation.The choice of the formulation is justified.
The product is an established pharmaceutical form and its development is adequately described
in accordance with the relevant European guidelines.
Active Substance
The active substance is pimobendan, an established active substance described in the
European Pharmacopoeia. The active substance is manufactured in accordance with the
principles of good manufacturing practice. The active substance specification is considered
adequate to control the quality of the material.
Other Substances
Citric acid anhydrous, maize starch, lactose monohydrate, povidone K25, croscarmellose
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Product Name: Vetmedin 5.0mg Flavour Tablets
MA Holder: Boehringer Ingelheim Ltd
sodium, anhydrous colloidal silica, magnesium stearate and purified water are appropriately
required to comply with the requirements of the current monograph of the European
Artificial beef flavour manufactured to an in-house specification has been developed for this
non-compendial ingredient. The specification and the conventional test methods described are
considered adequate and appropriate.
Packaging Materials
A statement by the applicant certifies the compliance of the pack components with Commission
Directive 2002/72/EC concerning containers suitable for food use. White, opaque, high density
polyethylene containers of nominal capacity 150 ml and their white, opaque polypropylene,
child-resistant closures are subjected to appropriate testing for appearance, dimensions and
material of construction by IR spectroscopy.
Manufacture of the Finished Product
The product is manufactured fully in accordance with the principles of good manufacturing
practice from a licensed manufacturing site. Process validation data on the product have been
presented in accordance with the relevant European guidelines. Scientific data have been
provided and compliance with the Note for Guidance on Minimising the Risk of Transmitting
Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products has
been satisfactorily demonstrated.
Finished Product Quality Control
The finished product specification controls the relevant parameters for the pharmaceutical form.
The tests in the specification, and their limits, have been justified and are considered
appropriate to adequately control the quality of the product. Tests include appearance, identity
tests, loss on drying, hardness, disintegration, uniformity of dosage, assay, degradation
products, dissolution and microbial purity.
Satisfactory validation data for the analytical methods have been provided. Batch analytical
data from the proposed production site have been provided demonstrating compliance with the
Stability of the Product
Stability data on the active substance have been provided in accordance with applicable
European guidelines, demonstrating the stability of the active substance when stored under the
approved conditions.
Stability data on the finished product have been provided in accordance with applicable
European guidelines, demonstrating the stability of the product throughout its shelf life when
stored under the approved conditions.
Other information:
Shelf life: 3 years
Storage conditions:
Do not store above 25oC.
Keep the container tightly closed.
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Product Name: Vetmedin 5.0mg Flavour Tablets
MA Holder: Boehringer Ingelheim Ltd
As this application is a line extension of an existing authorisation, the applicant has not
submitted a Part III dossier but has made cross-reference to the dossier for the currently
authorised capsule form Vetmedin 5.0 mg. An updated user risk assessment has been
User Safety
Pimobendan was developed for human use and has been licensed in Japan for human use
since September 1994. The human therapeutic dose is 2.5 mg twice per day, which is
equivalent to one of the 5 mg tablets, and the applicant has reported that there have been no
human suspected adverse reactions since the product was marketed in 1997.
The laboratory animal studies indicate that pimobendan is not mutagenic, carcinogenic,
teratogenic or a skin sensitizer. Although there are no data on eye/skin irritation potential of
pimobendan alone or the formulation, the exposure will be from handling the tablets and should
be negligible under normal circumstances of use, so no special user warnings are required.
In the event of ingestion of a single 5 mg tablet by an adult, study data in male volunteers
demonstrated that a slight fall in blood pressure and increase in heart rate may occur. It is not
clear if women would be more susceptible than men to the same dose as no studies in females
have been submitted. However, if a child ingests one or more tablets (and if more than one
tablet is consumed by an adult), more adverse effects would be experienced, such as a marked
fall in arterial blood pressure, severe headaches and palpitations with possible orthostatic
collapse, vomiting and diarrhoea.
The tablets are packed in opaque white tubs with child resistant closures. The tub will be
packaged in a cardboard box with a package leaflet. This packaging will minimise the exposure
to children and reduce the risk of accidental ingestion. The warnings on the SPC and package
leaflet are considered adequate to ensure safety to users of the product.
In the case of accidental ingestion, seek medical advice immediately and show the package
leaflet to the physician.
The applicant has not provided an update of the environmental risk assessment as there is no
change to the target animals, the indications, the dose administered or the duration of treatment
to the currently authorised capsule presentation. As a result environmental exposure will remain
the same.
Warnings and precautions as listed on the product literature are adequate to ensure safety to
the environment when the product is used as directed.
Disposal advice on SPC:
Any unused product or waste material derived from such veterinary medicinal product should be
disposed of in accordance with local requirements.
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Product Name: Vetmedin 5.0mg Flavour Tablets
MA Holder: Boehringer Ingelheim Ltd
IV.A Pre-Clinical Studies
The pharmacodynamics for pimobendan and its active metabolite have been well documented
and assessed as adequate for the original applications (Authorisations Vm 00015/4049, 4050
and 4066). This line extension is for the 5 mg capsules which was an application by informed
consent and therefore the applicant refers back to the data supporting the original application.
This is considered adequate for this line extension.
Information provided is reflected in the SPC:
Pimobendan, a benzimidazole-pyridazinone derivative, is a non-sympathomimetic, nonglycoside inotropic substance with potent vasodilatative properties.
Pimobendan exerts its stimulatory myocardial effect by a dual mechanism of action: increase in
calcium sensitivity of cardiac myofilaments and inhibition of phosphodiesterase (type III). It also
exhibits a vasodilating action through an inhibitory action on phosphodiesterase III activity.
The combined evidence from cell culture, laboratory animal and small studies in the target
species suggests that the combination of the specific PD properties of pimobendan may reduce
the progression of myocardial damage in dogs with MVD and DCM when used together with
other standard therapy.
Information of this nature is provided on the SPC:
Following oral administration of pimobendan, the absolute biovailability of the active principle is
60 - 63 %. Since this bioavailability is considerably reduced when pimobendan is administered
with food or shortly thereafter, it is recommended to treat animals approximately 1 hour before
The volume of distribution is 2.6 l/kg, indicating that pimobendan is distributed readily into the
tissues. The mean plasma protein binding is 93 %.
The compound is oxidatively demethylated to its major active metabolite (UD-CG 212). Further
metabolic pathways are phase II conjugates of UD-CG 212, in essence glucuronides and
The plasma elimination half-life of pimobendan is 0.4 + 0.1 hours, consistent with the high
clearance of 90 + 19 ml/min/kg and a short mean residence time of 0.5 + 0.1 hours.
Tolerance in the Target Species of Animals
The applicant has supported target species tolerance of the product in healthy dogs by
providing a study using the final formulation of up to 5 times the recommended dose for 6
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Product Name: Vetmedin 5.0mg Flavour Tablets
MA Holder: Boehringer Ingelheim Ltd
A number of observations and measurements were taken. Parameters evaluated included
clinical observations, physical examinations, body weights, urinanalysis, food consumption,
electrocardiography, indirect blood pressure, glucose levels, ophthalmic examination, gross
patholiogy and histopathology. The study concluded that the test product had the following
effects on the target organ, the heart. It increased maximum heart rate in a non-dose
dependent manner, and it is the likely cause of murmurs and cardiac hypertrophy with
subendocardial ischaemic lesions in one dog at 3x and 2 dogs at 5x recommended treatment
dose. These effects are typical of positive inotropic and vasodilator drug toxicity in normal dogs
There were no effects of a pathological or toxicological consequence attributable to pimobendan
in dogs at the proposed dose (1x group). The multiple dose groups did show toxicological
effects, but no mortalities resulted from exaggerated pimobendan doses.
Clinical Studies
The applicant submitted a clinical field trial involving a number of dogs with congestive heart
failure, designed to show non-inferiority to the positive control product used, enalapril (an ACE
inhibitor). This trial concluded that Vetmedin Chewable Tablets are as efficacious as enalapril
at treating heart failure, but does not show that the Vetmedin Flavour Tablets would be
comparable to the Vetmedin capsules.
However, in addition the applicant submitted a randomised study comparing cardiovascular
function and electrocardiographic parameters in a number of conscious, healthy dogs after
administration of 0.25mg/kg Vetmedin Flavour Tablets or Vetmedin capsules. The parameters
measured have been justified as related to pharmacological/clinical end points as heart failure
and survival time through experimentally induced heart failure models represented in the
original Vetmedin Capsule dossier.
This study was a randomised, crossover design using dogs (50% male 50% female). The wash
out period was 7 days. Body weights ranged from 24 to 31 kg. No information on breed was
found in the study report.
The data were collected and analysed. Statistical evaluation was also performed. The results
showed that there was no difference in measured parameters between the two Vetmedin
formulations. No adverse events were recorded.
It was concluded that treatment with Vetmedin Flavour Tablets led to the same effects on
cardiovascular function and ECG parameters in conscious dogs as the Vetmedin Capsules.
They concluded that the two formulations could be assessed as clinically interchangeable.
The data submitted in the dossier demonstrate that when the product is used in accordance
with the Summary of Product Characteristics, the risk benefit profile for the target species is
favourable and the quality and safety of the product for humans and the environment is
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