UKPAR_402304

United Kingdom
Veterinary Medicines Directorate

Woodham Lane
New Haw

Addlestone
Surrey KT15 3LS
NATIONAL PROCEDURE
PUBLICLY AVAILABLE ASSESSMENT REPORT FOR A VETERINARY
MEDICINAL PRODUCT
Propentofylline 50 mg Film Coated Tablets for Dogs
Propentofylline 100 mg Film Coated Tablets for Dogs

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Propentofylline 50 mg Film Coated Tablets for Dogs Application for National Procedure
Propentofylline 100 mg Film Coated Tablets for Dogs Publicly Available Assessment Report
Norbrook Laboratories Limited

MODULE 1

PRODUCT SUMMARY

Name, strength and Propentofylline 50 mg Film Coated Tablets for Dogs
pharmaceutical form Propentofylline 100 mg Film Coated Tablets for Dogs

Applicant Norbrook Laboratories Limited
Station Works
Active substance(s) Newry
ATC Vetcode Co. Down, BT35 6JP
Target species Northern Ireland
Indication for use Propentofylline

QC04AD90

Dogs

For improvement in dullness, lethargy and overall
demeanour in dogs. Is particularly useful in older
dogs, where it may increase willingness to exercise
and exercise tolerance.

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Propentofylline 50 mg Film Coated Tablets for Dogs Application for National Procedure
Propentofylline 100 mg Film Coated Tablets for Dogs Publicly Available Assessment Report
Norbrook Laboratories Limited

MODULE 2

The Summary of Product Characteristics (SPC) for this product is available on
the Veterinary Medicines Directorate website (www.vmd.defra.gov.uk)

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Propentofylline 50 mg Film Coated Tablets for Dogs Application for National Procedure
Propentofylline 100 mg Film Coated Tablets for Dogs Publicly Available Assessment Report
Norbrook Laboratories Limited

MODULE 3

PUBLIC ASSESSMENT REPORT

Legal basis of original Application in accordance with Article 13 (1) of
application Directive 2001/82/EC as amended.

I. SCIENTIFIC OVERVIEW

These applications for national Marketing Authorisations for generic products
were submitted in accordance with Article 13 (1) of Directive 2001/82/EC as
amended by 2004/28/EC and Directive 2009/9/EC. The reference products are
Vivitonin 50 mg Tablets and Vivitonin 100 mg Tablets, marketed by Merial in the
UK since 1991 and 1994 respectively.

Propentofylline 50 mg film coated tablets for dogs and Propentofylline 100 mg
film coated tablets for dogs are indicated for use in dogs for the treatment of
dullness, lethargy and overall demeanour in dogs. The products are particularly
useful in older dogs, where they may increase willingness to exercise and
exercise tolerance. The dosage rate for Propentofylline 50 mg film coated
tablets for dogs is half a tablet per 5 kg bodyweight twice daily which is
equivalent to 6-10 mg propentofylline per kg bodyweight per day. Dogs of less
than 5 kg may receive quarter tablet twice daily. The dosage rate for
Propentofylline 100 mg film coated tablets for dogs is half a tablet per 10 kg
body weight twice daily. These tablets should not be quartered. More accurate
dosing may be achieved using a combination of Propentofylline 50 mg film
coated tablets for dogs and Propentofylline 100 mg film coated tablets for dogs.
The tablets can be administered directly onto the back of the dog’s tongue or
can be mixed in a small ball of food and should be administered at least 30
minutes before feeding.

The products are produced and controlled using validated methods and tests,
which ensure the consistency of the products released on the market. It has
been shown that the products can be safely used in the target species; the slight
reactions observed are indicated in the SPC1. The products are safe for the
user, and for the environment, when used as recommended. Suitable warnings
and precautions are indicated in the SPC. The efficacy of each product was
demonstrated according to the claims made in the SPC.

1 Summary of product characteristics

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Propentofylline 50 mg Film Coated Tablets for Dogs Application for National Procedure
Propentofylline 100 mg Film Coated Tablets for Dogs Publicly Available Assessment Report
Norbrook Laboratories Limited

II. QUALITY ASPECTS

A. Composition

Propentofylline 50 mg Film Coated Tablets for Dogs
The product contains 50 mg per tablet propentofylline as an active substance
and opadry ll Blue 85G30552, white maize starch, lactose monohydrate,
povidone K30, croscarmellose sodium, purified water, talc, silica colloidal
anhydrous, magnesium stearate and microcrystalline cellulose as excipients.
The product is supplied in cartons of 30 tablets presented in
polyvinylchloride/aluminium strip pack each containing 15 tablets.

Propentofylline 100 mg Film Coated Tablets for Dogs
The product contains 100 mg per tablet propentofylline as an active substance
and opadry ll Blue 85G30552, white maize starch, lactose monohydrate,
povidone K30, croscarmellose sodium, purified water, talc, silica colloidal
anhydrous, magnesium stearate and microcrystalline cellulose as excipients.
The product is supplied in cartons of 60 tablets presented in
polyvinylchloride/aluminium strip pack each containing 10 tablets.

The particulars of the containers and controls performed are provided and
conform to the regulation.

The choice of the formulation is justified.

B. Method of Preparation of the Product

The products are manufactured fully in accordance with the principles of good
manufacturing practice from a licensed manufacturing site.

Process validation data on the products have been presented in accordance with
the relevant European guidelines.

C. Control of Starting Materials

The supporting data for propentofylline have been provided in the form of
EDQM2. It is considered that the manufacturing process is adequately controlled
and the active substance specifications have been suitably justified.

There are ten excipients used in the formulation and each has been used
previously in veterinary medicines. White maize starch, lactose monohydrate,
povidone K30, croscarmellose sodium, purified water, talc, silica colloidal
anhydrous, magnesium stearate and microcrystalline cellulose have

2 The European Directorate for the Quality of Medicines & HealthCare.

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Propentofylline 50 mg Film Coated Tablets for Dogs Application for National Procedure
Propentofylline 100 mg Film Coated Tablets for Dogs Publicly Available Assessment Report
Norbrook Laboratories Limited

monographs in the European Pharmacopoeia and each complies with the
requirements of the current edition of the Ph. Eur.

The applicant provided raw material specifications for opadry II Blue 85G30552.
This is considered acceptable.

D. Specific Measures concerning the Prevention of the Transmission
of Animal Spongiform Encephalopathies

There are no substances within the scope of the TSE Guideline present or used
in the manufacture of this product.

E. Control on intermediate products
There are no intermediate products.

F. Control Tests on the Finished Product

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.

Satisfactory validation data for the analytical methods have been provided.

G. Stability

Stability data on the active substances have been provided in accordance with
applicable European guidelines, demonstrating the stability of the product
throughout its shelf-life. The shelf-life of the veterinary medicinal product as
packaged for sale is 18 months. Any remaining half tablet portions should be
discarded.

H. Genetically Modified Organisms
Not applicable.

J. Other Information

A shelf-life of 18 months is justified subject to the following storage precautions:

 Do not store above 25°C.
 Store in a dry place.

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Propentofylline 50 mg Film Coated Tablets for Dogs Application for National Procedure
Propentofylline 100 mg Film Coated Tablets for Dogs Publicly Available Assessment Report
Norbrook Laboratories Limited

 Keep blister packs in outer carton.

III. SAFETY AND RESIDUES ASSESSMENT (PHARMACO-
TOXICOLOGICAL)

III.A Safety Testing

Pharmacological Studies

Since these generic applications were made in accordance with Article 13 (1) of
Directive 2001/82/EC as amended by Directive 2004/28/EC, data on
pharmacodynamics and pharmacokinetics were not required. However, the
applicant has submitted six pharmacokinetic studies in the target species. These
studies are reported in Part IV of this report.

Toxicological Studies

Since these generic applications were made in accordance with Article 13 (1) of
Directive 2001/82/EC as amended by Directive 2004/28/EC, data on toxicology
were not required. However, the applicant has submitted a tolerance study in
the target species. This study is reported in Part IV of this report.

Other Studies

Since these generic applications were made in accordance with Article 13 (1) of
Directive 2001/82/EC as amended by Directive 2004/28/EC, data on toxicology
were not required. However, the applicant has submitted published literature
regarding observations in humans and studies on identified metabolites.

Observations in Humans

The applicant has provided data which indicated that propentofylline can be
administered to humans at therapeutic doses with only minor adverse effects.

User Safety

The following operator warnings are included in the SPC and product literature:

 Care should be taken to avoid accidental ingestion.
 In the event of accidental ingestion, seek immediate medical advice and

show the package leaflet to the doctor.
 Wash hands after use.

Ecotoxicity

The applicant provided a first phase environmental risk assessment in
compliance with the relevant guideline.

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Propentofylline 50 mg Film Coated Tablets for Dogs Application for National Procedure
Propentofylline 100 mg Film Coated Tablets for Dogs Publicly Available Assessment Report
Norbrook Laboratories Limited

The assessment ended at Phase I as the products will only be used in dogs and
exposure of the environment is not sufficient to require further assessment. The
warnings and precautions as listed on the product literature are adequate to
ensure safety to the environment when the product is used as directed.

IV CLINICAL ASSESSMENT (EFFICACY)

IV.A Pre-Clinical Studies

Pharmacology

Pharmacodynamics
The applicant submitted several references and a summary of the
pharmacodynamic effects of propentofylline. Propentofylline has been shown to
increase the blood flow, particularly of the heart and skeletal muscle. It also
increases the blood flow of the brain and therefore its oxygen supply, without
increasing the brain’s glucose demand. It has modest positive chronotropic
effect and a marked positive ionotropic effect. In addition, it has been shown to
have an anti-arrhythmic effect in dogs with myocardial ischemia and a
bronchodilator action equivalent to that of aminofylline.
Propentofylline inhibits platelet aggregation and improves the flow properties of
erythrocytes. It has a direct effect on the heart and reduces peripheral vascular
resistance thereby lowering cardiac load.

Pharmacokinetics
The applicant submitted five bioequivalence studies and one study
demonstrating the pharmacokinetics of the reference product, Vivitonin. The two
studies were not conducted using the final formulation. The other two studies
were also preliminary studies and were not GLP3-compliant. Only one study was
considered the pivotal, GLP-compliant study. This comparative study of plasma
levels of propentofylline and its hydroxylated metabolite was conducted in dogs
following the oral administration of Propentofylline 50 mg film coated tablets and
Vivitonin 50 mg tablets. This was a randomised, single-dose, two-treatment,
two-period crossover bioequivalence study with a wash out period of 34 days. A
suitable number of dogs were divided into two treatment groups based on weight
and sex and subsequently given either the test product Propentofylline 50 mg
film coated tablets for dogs or the reference product Vivitonin 50 mg tablets.
The dosage rate was half a tablet per 5 kg bodyweight. Blood sampling was
performed during the trial, with plasma levels of both test and reference product
being compared with regard to active substance and its hydroxylated metabolite.
The study concluded that Propentofylline film coated tablets for dogs were
bioequivalent to Vivitonin 50 mg tablets.

3 Good laboratory practice

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Propentofylline 50 mg Film Coated Tablets for Dogs Application for National Procedure
Propentofylline 100 mg Film Coated Tablets for Dogs Publicly Available Assessment Report
Norbrook Laboratories Limited

Tolerance in the Target Species of Animals

The applicant conducted a target animal safety study in dogs following the oral
administration of the test product. The study was conducted in accordance with
GLP. This was a randomised, blinded, placebo-controlled, single-phase, parallel
study conducted on a suitable number of dogs. The dogs were divided into
different groups. All dogs were subject to clinical monitoring throughout the
study. The product did not cause any significant evidence of intolerance when
administered at five times the proposed dose for ten days or at the proposed
dose for 90 days. The study concluded that the test product was well tolerated
in dogs under field conditions.

IV.B Clinical Studies

Since these generic applications were made in accordance with Article 13 (1) of
Directive 2001/82/EC as amended by Directive 2004/28/EC, the applicant has
not conducted any dose confirmation or field studies with the final formulation.
The applicant provided a review of published literature. No further clinical data is
required.

V OVERALL CONCLUSION AND BENEFIT– RISK ASSESSMENT

The data submitted in the dossier demonstrate that when the product is used in
accordance with the Summary of Product Characteristics, the benefit/risk profile
for the target species is favourable and the quality and safety of the product for
humans and the environment is acceptable.

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Propentofylline 50 mg Film Coated Tablets for Dogs Application for National Procedure
Propentofylline 100 mg Film Coated Tablets for Dogs Publicly Available Assessment Report
Norbrook Laboratories Limited

MODULE 4

POST-AUTHORISATION ASSESSMENTS
The SPC and package leaflet may be updated to include new information on the
quality, safety and efficacy of the veterinary medicinal product. The current SPC
is available on the Product Information Database of the Veterinary Medicines
Directorate website.
(www.gov.uk/check-animal-medicine-licensed)

The post-authorisation assessment (PAA) contains information on significant
changes which have been made after the original procedure which are important
for the quality, safety or efficacy of the product.

The PAA for this product is available on the Product Information Database of the
Veterinary Medicines Directorate website.
(www.gov.uk/check-animal-medicine-licensed)

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