Eprecis Injection for Beef and Dairy Cattle is used for the treatment of and control of gastro-intestinal worms (including inhibited Ostrtagia ostertagia and Cooperia spp.), lungworms, warbles, sucking lice, chorioptic and sarcoptic mange mites in beef and dairy cattle. Eprecis Injection has no withdrawl time for dairy cattle. The Herd pack contains 2 X 250ml bottles, 1 X 100ml bottle plus a free injector.
Active Ingredient: Eprinomectin
Target Species: Cattle
Treats and Controls: Gastro-intestinal worm, lungworm, sucking and biting lice and mange mites
Administration Method: Subcutaneous Injection
Withdrawal Time: 63 days for cattle intended for meat and offal, there is no withdrawal time for cattle producing milk for human consumption.
Dosage: 1 ml per 100 kg of bodyweight.
|Body Weight||Dose Volume||Number of full doses per pack:|
Always read the label and all enclosed information for Eprecis Injection before administering to animals!
This product is only licensed for sale within the Republic of Ireland
The public assessment report reflects the scientific conclusion reached by the HPRA at the end of the evaluation
process and provides a summary of the grounds for approval of the marketing authorisation for the specific veterinary
medicinal product. It is made available by the HPRA for information to the public, after the deletion of commercially
confidential information. The legal basis for its creation and availability is contained in Article 25.4 of EC Directive
2001/82/EC as amended by Directive 2004/28/EC for veterinary medicinal products. It is a concise document which
highlights the main parts of the documentation submitted by the applicant and the scientific evaluation carried out by
the HPRA leading to the approval of the product for marketing in Ireland.
The Summary of Product Characteristics (SPC) for this product is available on the HPRA’s website.
I SCIENTIFIC OVERVIEW
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 product is safe for the user, the consumer of foodstuffs from treated animals 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 benefit/risk analysis is in favour of granting a marketing authorisation.
II QUALITY ASPECTS
A. Qualitative and Quantitative Particulars
The product contains eprinomectin (20 mg/ml) and the excipients butylhydroxytluene (E321), dimethyl sulfoxide and
EU Procedure number IE/V/0340/001/DC
Name, strength and pharmaceutical form Eprecis 20 mg/ml solution for injection for cattle
Active substance(s) Eprinomectin
Applicant Ceva Santé Animale
10 Av. de la Ballastiere
Legal basis of application “Hybrid” application in accordance with Article 13 (3.) of Directive
2001/82/EC as amended.
Date of authorisation
Cattle (beef and dairy cattle).
Indication for use Treatment of infestations by listed internal and external parasites
sensitive to eprinomectin, prevention of reinfestations with various
species of parasites.
ATCvet code QP54AA04
Concerned Member States
AT, BE, BG, CY, CZ, DE, DK, EE, EL, ES, FI, FR, HU, IT, LT, LU,
LV, MT, NL, PL, PT, RO, SE, SI, SK, UK
Health Products Regulatory Authority
Date Printed 11/09/2015 CRN 7017149 page number: 2
glycerol formal stabilised.
The product is presented in 50 ml, 100 ml, 250 ml or 500 ml amber multilayer plastic vials with bromobutyl rubber
stoppers and aluminium and plastic flip capsules.
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.
B. Method of Preparation of the Product
The product is manufactured fully in accordance with the principles of good manufacturing practice at a licensed
Process validation data for the manufacturing process has been presented in accordance with the relevant European
C. Control of Starting Materials
The active substance is eprinomectin an established active substance. 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. Batch analytical data
demonstrating compliance with this specification has been provided.
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.
D. Control on Intermediate Products
E. 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
Satisfactory validation data for the analytical methods has been provided.
Batch analytical data from the proposed production site has been provided demonstrating compliance with the
Stability data on the active substance has 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 has been provided in accordance with applicable European guidelines,
demonstrating the stability of the product throughout its shelf life when stored under the approved conditions.
G. Other Information
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III SAFETY AND RESIDUES ASSESSMENT (PHARMACO-TOXICOLOGICAL)
The application for marketing authorisation was submitted in accordance with Article 13 (3.) (“hybrid” application) of
Directive 2001/82/EC as amended (“ […] in the case of changes to the active substance(s), therapeutic indications,
strength, pharmaceutical form or route of administration vis-à-vis the reference medicinal product […].”) The reference
product chosen by the applicant is Eprinex 0.5% w/v pour-on solution for beef and dairy cattle (Merial, Ireland) for
which the following differences, relative to the reference medicinal product, have been identified:
- change in pharmaceutical form (from pour-on solution to solution for injection)
- change in strength (quantitative change to the active substancefrom 5mg/ml to 20 mg/ml)
- change in route of administration (from pour-on use to subcutaneous use)
The product is intended to be injected to cattle by subcutaneous route at the dose rate of 0.2mg of eprinomectin/kg bw
(i.e.: 1 ml/100 kg BW) as single injection.
III.A Safety Testing
The applicant has provided bibliographical data which show that eprinomectin acts by binding selectively and with
high affinity to glutamate-gated chloride ion channels which occur in invertebrate nerve or muscle cells. This leads to
an increase in the permeability of the cell membrane to chloride ions with hyperpolarisation of the nerve or muscle cell,
resulting in paralysis and death of the parasite. Compounds of this class may also interact with other ligand-gated
chloride channels, such as those gated by the neurotransmitter gamma-aminobutyric acid (GABA). The margin of
safety for compounds of this class is attributable to the fact that mammals do not have glutamate-gated chloride
channels; the macrocyclic lactones have a low affinity for other mammalian ligand-gated chloride channels, and they
do not readily cross the blood-brain barrier.
In support of this application, the applicant conducted an in vivo study in order to compare the bioavailability of the
product and the reference product (Eprinex 0.5% pour on solution for beef and cattle). Please refer to Section IV.A for
Information on toxicity of eprinomectin is sourced primarily from MRL summary reports published by EMA and
JECFA. Given that the majority of the data presented has been reviewed by the CVMP in the context of the MRL
assessment, it is accepted that the toxicity of eprinomectin has been adequately characterised. In brief:
· Eprinomectin has moderate acute toxicity with a LD50 value of 35mg/kg BW in the mouse and in the rat,
using the intraperitoneal route.
· In the dog, a NOEL of 1mg/kg b.w. was established after repeated oral administration of eprinomectin for 6
or 53 weeks, based on mydriasis and focal neuronal degeneration in the brain.
· Repeated oral doses in pregnant rats and rabbits have not revealed any evidence of embryo- or foeto-toxic
potential for eprinomectin.
· Eprinomectin did not show genotoxic activity in a battery of tests.
· Eprinomectin is not considered to have carcinogenic potential.
The applicant has provided a series of local effect studies conducted using the final formulation. Based on these studies,
the formulation proposed for marketing is considered neither a skin irritant nor a skin sensitiser. However, the test item
is considered an ocular irritant.
Observations in Humans
No human data are available as eprinomectin has been developed exclusively for use in veterinary medicine. However,
other substances of the avermectin family have been used in humans, e.g.: ivermectin. In humans ivermectin is
administered orally as a single dose of 200μg/kg BW. Ivermectin is generally well tolerated; however, adverse effects
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Date Printed 11/09/2015 CRN 7017149 page number: 4
can occur and are usually mild-to-moderate in nature and transient.
The applicant has provided a user safety assessment in compliance with the relevant guideline. The product includes as
excipients buthyl hydroxy toluene (BHT), dimethyl sulfoxide (DMSO) and glycerol formal stabilised. These are
common excipients and, in terms of potential hazard, are considered of minor importance compared to the active
ingredient eprinomectin. It was shown that a potential risk for the user may arise following accidental oral, dermal,
systemic or ocular exposure to the formulation. The SPC includes a number of user safety warnings in order to
mitigate against such risks. Warnings and precautions as listed on the product literature are considered adequate to
ensure safety to users of the product.
Environmental Risk Assessment
A Phase II ERA is required as the target species are reared on pasture, and eprinomectin is an endo- & ectoparasiticide.
The applicant provided a comprehensive data package on the environmental fate and toxicity of eprinomectin. Using
those study data, the applicant presented a detailed ERA. The risk assessment highlights potential risks for dung
dwelling organisms exposed to dung produced by treated pasture animals, surface water in the case of direct excretion
and indirect exposure from run-off events and sediment in the case of direct excretion. The risks identified are as
expected for this class of compound (macrocyclic lactones) and, with a view to reducing the risks identified, risk
mitigation measures similar to those accepted for related products have been included in the SPC and on product
III.B Residues Documentation
Two studies were conducted in the target species to characterise depletion of residues from meat and milk following
administration of the final formulation. Both studies were conducted in accordance with GLP and relevant guidance.
The analytical method used for determination of eprinomectin residues in tissues/milk was appropriately validated.
Eprinomectin is listed in Table I of the Annex to Commission Regulation (EU) No 37/2010 as follows:
Based on the residue data provided, withdrawal periods of 63 days for meat in cattle and 0 days for milk are justified.
IV CLINICAL ASSESSMENT (EFFICACY)
IV.A Pre-Clinical Studies
Muscle 50 μg/kg
Liver 1,500 μg/kg
Kidney 300 μg/kg
Fat 250 μg/kg
Milk 20 μg/kg
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In order to adequately characterise the pharmacokinetics of eprinomectin, the applicant has conducted proprietary
studies and has provided bibliographical data which are summarised as follows:
• Following subcutaneous administration of eprinomectin at a dose of 0.2 mg/kg, plasma concentrations increased
rapidly to reach a peak (mean Cmax: 58.0 ± 17.80μg/L) between 24hr and 72hr after dosing (median Tmax: 36hr).
• Systemic exposure after subcutaneous administration at 0.2mg eprinomectin/kg was approximately 2 times higher
than that observed after pour-on administration of 0.5 mg/kg without any dose normalisation. However,
eprinomectin is slower to deplete from plasma following topical administration compared to following
subcutaneous administration: the elimination half-life following topical administration was calculated to be
115.06+29.01 hr compared to 65.33+23.51 hr following subcutaneous administration.
• Over the dose range 0.1 to 0.4 mg/kg, eprinomectin exhibits linear pharmacokinetics. In addition, following
repeated administration at intervals of one week, clinically relevant systemic accumulation was not evident.
• The absolute bioavailability of eprinomectin of the subcutaneous formulation was about 89% (range: 75% -
• Macrocyclic lactones have a high lipophilicity. They are distributed extensively throughout the body and
concentrate particularly in adipose tissue.
• Eprinomectin is highly bound (greater than 99%) to cattle plasma proteins.
• Eprinomectin is not extensively metabolised in cattle and is excreted primarily in faeces. There is very limited
elimination of eprinomectin in milk.
Tolerance in the Target Species of Animals
Th e a p p l i c a n t evaluated the general and local tolerance of the test item in cattle in a GLP study which followed the
general recommendations of VICH GL43. Based on the findings of the study, it is accepted that systemic tolerance to
the product is good/acceptable when administered 3 times at weekly intervals at up to 5 times the recommended
treatment dose. However, local reactions at the site of injection are very common. These reactions are characterised by
moderate to severe swelling followed by induration. Swelling may last for up to one week, with induration persisting
for in excess of two weeks. Swelling may be associated with mild to moderate pain.
Regarding reproductive safety, it is accepted, based on bibliographic data provided, that eprinomectin is not a teratogen
when investigated in laboratory animals and had no negative impact on reproductive parameters in cattle when
administered topically at a dose of 1.5 mg eprinomectin/kg (3X the recommended topical dose). Given that topical
administration of 1.5 mg eprinomectin/kg had no effect on pregnant or breeding cattle and that systemic availability
following subcutaneous administration of 0.2 mg eprinomectin/kg will likely be less that that achieved following
topical administration of 1.5 mg eprinomectin/kg, it is accepted that 0.2 mg eprinomectin/kg administered by the
subcutaneous route will not pose a risk to pregnant or breeding cattle. A restriction on use in pregnant or breeding cattle
is not required.
The product literature accurately reflects the type and incidence of adverse effects which might be expected.
Adequate warnings and precautions appear on the product literature:
Care should be taken to avoid the following practices because they increase the risk of development of resistance and
could ultimately result in ineffective therapy:
Too frequent and repeated use of anthelmintics from the same class, over an extended period of time.
Underdosing, which may be due to underestimation of bodyweight, misadministration of the product, or lack
of calibration of the dosing device (if any).
Suspected clinical cases of resistance to anthelmintics should be further investigated using appropriate tests (e.g. Faecal
Egg Count Reduction Test). Where the results of the test(s) strongly suggest resistance to a particular anthelmintic, an
anthelmintic belonging to another pharmacological class and having a different mode of action should be used.
To date no resistance to eprinomectin (a macrocyclic lactone) has been reported within the EU. However resistance to
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Date Printed 11/09/2015 CRN 7017149 page number: 6
other macrocyclic lactones has been reported in parasite species in cattle within the EU. Therefore, use of this product
should be based on local (regional, farm) epidemiological information about susceptibility of nematodes and
recommendations on how to limit further selection for resistance to anthelmintics.
IV.B Clinical Studies
It is noted that the applicant had requested and received Scientific Advice from the European Medicines Agency on
data requirements to support efficacy and aspects of target animal safety. As part of this scientific advice, the CVMP
agreed certain approaches to establishing efficacy and this advice has been taken into account in the assessment of the
Eprinomectin has been authorised in the Community since 1997 for use in cattle as a pour-on formulation for topical
application at a dose of 0.5 mg/kg (Eprinex® Pour-on). Consequently, it is argued that the efficacy profile/spectrum of
activity of eprinomectin is well established. Efficacy of the pour-on formulation is supported by reference to
information in the published domain.
A study was conducted to characterise the eprinomectin plasma pharmacokinetic profile following administration of
eprinomectin to cattle by the intravenous, subcutaneous and topical routes. Based on the outcome of this comparative
pharmacokinetic study, systemic exposure after subcutaneous administration at 0.2 mg eprinomectin/kg was
approximately 2 times higher than that observed after pour-on administration of 0.5 mg/kg without any dose
normalisation. Given the higher systemic availability, it is expected that the test product at the proposed dose of 0.2 mg
eprinomectin/kg will be at least as effective as the authorised reference product, Eprinex Pour-on Solution, for the
treatment of lungworm (Dictyocaulus viviparous) and gastrointestinal nematodes.
The efficacy of eprinomectin against lungworm and common gastrointestinal nematodes when administered by the
subcutaneous route at a dose of 0.2 mg/kg is further supported by a study reported in the scientific literature and a
single confirmatory study conducted using the formulation proposed for marketing. Although only a single
confirmatory study using the product proposed for marketing was conducted by the applicant, the study did evaluate
efficacy against the dose-limiting nematode species and adequate efficacy (in accordance with guideline requirements)
was confirmed. Given the well-established efficacy of the active substance and the other data presented in support of
efficacy, a single confirmatory study is considered adequate.
In addition to the nematode indication it is also accepted, based on the data/argumentation presented, that the claim for
efficacy against sucking lice (Linognathus vituli, Haematopinus eurysternus, Solenopotes capillatus), horn flies
(Haematobia irritans), Sarcoptes scabiei var. bovis and Hypoderma spp. has been adequately justified (bibliographic
data and, based on the comparative pharmacokinetic study, efficacy for these parasite species can be extrapolated from
the authorised pour-on product, Eprinex.
In addition to the indication for treatment of infestation, available data support a claim for the prevention of
reinfestation with certain nematodes for periods up to 14 days. The duration of persistent effect (14 days) was accepted
based on the findings of the comparative pharmacokinetic study. In that study, the mean plasma concentration at 336
hours (14 days) following subcutaneous administration was less than the mean plasma concentration detected following
topical administration. However, the mean/range of plasma concentrations at 336 hours following subcutaneous
administration (3.80 microgram/L [0.63 – 10.54]) exceeds the mean/range of plasma concentrations at 480 hours (20
days) following topical administration (1.64 microgram/L [0.64-3.02]). Given that the authorised pour-on product
claims persistent efficacy against a range of target nematodes for 21-28 days following treatment, it follows that
systemic exposure over this time frame is adequate for effect (that is, plasma concentrations in the range 0.64-3.02
microgram/L correlate with adequate efficacy). Therefore, it can be accepted that the systemic exposure at 14 days
following administration of the injectable eprinomectin product will be adequate for effect against the claimed
No field studies have been presented. Given that the active substance is well established, the CVMP in the context of a
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Date Printed 11/09/2015 CRN 7017149 page number: 7
scientific advice procedure agreed that field studies investigating efficacy would not be required where the findings of
the comparative pharmacokinetic study confirmed comparable, or superior, systemic availability for the injectable
formulation compared to the authorised pour-on formulation.
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.
VI 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 HPRA website.
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.
Health Products Regulatory Authority
Date Printed 11/09/2015 CRN 7017149 page number: 8
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