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

Propentofylline 100 mg Film Coated Tablets for Dogs

Norbrook Laboratories Limited Application for National Procedure

Publicly Available Assessment Report

MODULE 1

PRODUCT SUMMARY

Name, strength and pharmaceutical form / Propentofylline 50 mg Film Coated Tablets for Dogs
Propentofylline 100 mg Film Coated Tablets for Dogs
Applicant / Norbrook Laboratories Limited
Station Works
Newry
Co. Down, BT35 6JP
Northern Ireland
Active substance(s) / Propentofylline
ATC Vetcode / QC04AD90
Target species / Dogs
Indication for use / 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.


MODULE 2

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


MODULE 3

PUBLIC ASSESSMENT REPORT

Legal basis of original application / Application in accordance with Article 13 (1) of 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 SPC[1]. 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.

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 EDQM[2]. 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 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.

·  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.

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 GLP[3]-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.

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.

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 Veterinary Medicines Directorate website (www.vmd.defra.gov.uk)

This section 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.

·  / 23 May 2012 / Change in immediate packaging of the finished product.
·  / 23 May 2012 / Change in immediate packaging of the finished product.

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[1] Summary of product characteristics

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

[3] Good laboratory practice