United Kingdom
Veterinary Medicines Directorate
Woodham Lane
New Haw
Addlestone
Surrey KT15 3LS
NATIONAL PROCEDURE
PUBLICLY AVAILABLE ASSESSMENT REPORT FOR A VETERINARY
MEDICINAL PRODUCT
Apometic 10 mg/ml Solution for Injection
1/12
Apometic 10 mg/ml Solution for Injection
Forum Products Limited
Application for National Procedure
Publicly Available Assessment Report
MODULE 1
PRODUCT SUMMARY
Name, strength and
pharmaceutical form
Apometic 10 mg/ml Solution for Injection
Applicant
Forum Products Limited
Crown House
2-8 Gloucester Road
Redhill
Surrey
RH1 1FH
Active substance(s)
Apomorphine Hydrochloride
ATC Vetcode
QN04BC07
Target species
Dogs
Indication for use
To induce emesis in dogs that have, or are
suspected to have, ingested substances that
may be poisonous.
VMD/L4/GAT/014/C
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Apometic 10 mg/ml Solution for Injection
Forum Products Limited
Application for National Procedure
Publicly Available Assessment Report
MODULE 2
The Summary of Product Characteristics (SPC) for this product is available on
the Veterinary Medicines Directorate website (www.vmd.defra.gov.uk)
VMD/L4/GAT/014/C
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Apometic 10 mg/ml Solution for Injection
Forum Products Limited
Application for National Procedure
Publicly Available Assessment Report
MODULE 3
PUBLIC ASSESSMENT REPORT
Legal basis of original
application
Exceptional limited marketing application in
accordance with the Veterinary Medicine
Regulations.
I. SCIENTIFIC OVERVIEW
Apometic 10 mg/ml Solution for Injection has an Exceptional Limited Marketing
Authorisation. This type of MA is granted as there is a therapeutic gap in the UK
for the indication, induction of emesis in dogs, because there are no products
authorised with a full MA. The product is only for use when poisoning is
suspected in dogs.
The product contains apomorphine hydrochloride and is indicated for emesis in
dogs. The proposed dose rate is 0.2 mg per kg body weight and administration
is by subcutaneous injection. The product is contraindicated for use in cats and
other species, in cases where hypersensitivity to apomorphine or an excipient is
known, in cases of pyrethroid or caustic poisoning or where gastric foreign
bodies may be present and in cases where there is depression of the Central
Nervous System (CNS).
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 SPC1.
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 benefit/risk analysis is in favour of granting a marketing
authorisation.
II.
QUALITY ASPECTS
A.
Composition
The product contains the active substance apomorphine hydrochloride and the
excipients sodium metabisulphite, hydrochloric acid, sodium hydroxide and
water for injections.
1
SPC – Summary of Product Characteristics
VMD/L4/GAT/014/C
4/12
Apometic 10 mg/ml Solution for Injection
Forum Products Limited
Application for National Procedure
Publicly Available Assessment Report
The container/closure system consists of 2 ml of product packaged into clear
glass ampoules in cardboard boxes of 2 or 5 ampoules. 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.
B.
Method of Preparation of the 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. The product is manufactured, following sterilisation of the
vessel and filling parts, by replacing the air with nitrogen then dissolving the
apomorphine hydrochloride with the water for injections and then dissolving the
sodium metabisulphite and checking or adjusting the pH. The volume is then
adjusted and the remaining excipients mixed, and the pH checked, before
sterilisation and filling of sterilised ampoules.
C.
Control of Starting Materials
The active substance is apomorphine hydrochloride, an established active
substance described in the European Pharmacopoeia (Ph. Eur). 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 have been provided.
All excipients comply with their respective Ph. Eur monographs. Certificates of
analysis were received from each manufacturer, and testing of the excipients is
performed on receipt.
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
Not applicable.
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
VMD/L4/GAT/014/C
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Apometic 10 mg/ml Solution for Injection
Forum Products Limited
Application for National Procedure
Publicly Available Assessment Report
product. The tests include identification and assay of the active substance and
excipients, identification of impurities, pH and appearance.
Satisfactory validation data for the analytical methods have been provided.
Batch analytical data from the proposed production sites have been provided
demonstrating compliance with the specification.
G.
Stability
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. A retest period of 3 years
was established for both suppliers of the active substance.
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. A shelf life of
3 years is supported for the finished product.
H.
Genetically Modified Organisms
Not applicable.
J.
Other Information





The shelf life of the finished product as packaged for sale: 3 years.
The product is for single use only. Any unused solution should be
discarded.
Do not store above 25ºC.
Store in the original packaging to protect from light.
The solution should be visually inspected before use. Only clear and
colourless solution should be used.
III.
SAFETY AND RESIDUES
TOXICOLOGICAL)
III.A
Safety Testing
ASSESSMENT
(PHARMACO-
Pharmacological Studies
Pharmacodynamics
Apomorphine is a synthetic derivative of morphine and a dopaminergic agonist,
which primarily affects the hypothalamic region of the brain. It induces emesis by
stimulating post-synaptic dopamine (D2) receptors in the chemoreceptor trigger
zone (CTZ) in the brain.
Apomorphine does not have analgesic, opiate or addictive properties however
when given at higher doses it can act to suppress vomiting by stimulating the µ
receptors in the vomiting centre of the brain. Transient effects of apomorphine
VMD/L4/GAT/014/C
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Apometic 10 mg/ml Solution for Injection
Forum Products Limited
Application for National Procedure
Publicly Available Assessment Report
include reduction of blood pressure and body temperature, accompanied by an
increase in heart rate.
Pharmacokinetics
Following subcutaneous administration apomorphine hydrochloride is rapidly
absorbed and peak plasma concentrations are reached within 20-25 minutes.
Concentrations sufficient to induce emesis in dogs are reached within 10
minutes following injection.
Apomorphine is lipophilic and is extensively distributed to tissues. After injection
it rapidly diffuses across the blood-brain barrier. Apomorphine is extensively
metabolised in the liver by oxidation into non-active metabolites.
The metabolites of apomorphine, and a little unchanged apomorphine (<2%), is
excreted via the urine. Apomorphine has a short elimination half life in dogs of
30 – 64 minutes.
Toxicological Studies
As this is a Limited Marketing Authorisation the applicant has not conducted any
toxicity studies. However references have been provided for toxicity studies
conducted for the initial development of apomorphine as a human product and
for published literature in support of this application.

Single Dose Toxicity
The applicant has referred to an acute toxicity study performed in rats each
given a single dose of up to 30 mg/kg apomorphine subcutaneously. There were
no animal deaths at a dose of 30 mg/kg.

Repeated Dose Toxicity
A number of repeat dose toxicity studies have been referred to by the applicant.
The studies were performed in rats and monkeys. Male and female rats were
given daily doses of apomorphine four times daily for up to 13 weeks. The
monkeys received 6 doses per day for up to 39 weeks. In both studies any
changes in behaviour were monitored and observed.

Reproductive Toxicity, including Teratogenicity
A study included by the applicant looked at the possibility of apomorphine HCl
reproductive toxicity in male dogs. Male dogs were given apomorphine HCl via
the subcutaneous route every day for 6 months. No adverse effects were seen.

Mutagenicity
The applicant has provided in vitro and in vivo geneotoxicity tests. The Ames
test was performed indicating that the active substance was mutagenic. In
addition an in vitro Chromosomal aberration test was provided.
VMD/L4/GAT/014/C
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Apometic 10 mg/ml Solution for Injection
Forum Products Limited
Application for National Procedure
Publicly Available Assessment Report
In vivo studies included a mouse lymphoma assay and an in vivo chromosomal
aberration test, as well as investigating apomorphine induced DNA damage and
performing a mouse micronucleus assay. Some evidence of mutagenicity was
found during the mouse lymphoma assay at high levels of apomorphine.
However the other tests, in vivo chromosomal aberration test, DNA damage test
and micronucleus assay, were all negative for mutagenic effects.
The applicant has cited studies which concluded that apomorphine is genotoxic
in vitro, mainly due to the formation of free radical following its oxidation, but
there was no evidence of genotoxicity in vivo. This suggests genotoxicity is
unlikely but there is still the possibility of apomorphine causing mutagenic effects
due to the effects demonstrated in vitro.

Carcinogenicity
The applicant has provided a studythat investigates the carcinogenicity of
apomorphine. Studies indicate apomorphine is not mutagenic, nor carcinogenic.
In vivo studies were conducted where mice received the maximum tolerable
dose level of apomorphine and the results were negative for carcinogenic
effects.
Observations in Humans
The applicant has provided information on the use of apomorphine to treat
Parkinson’s disease in humans. They report the most frequent adverse effects
include nausea and vomiting, which can be controlled by domperidone, a
dopaminergic antagonist.
User Safety
The applicant has provided a user safety assessment in compliance with the
relevant guideline which shows that veterinarians are at most risk of exposure
and that the risk of exposure is low. The routes of possible exposure have been
identified as accidental needle stick injury or dermal contact following accidental
spillage. Ocular, oral or inhalation exposure has been identified as highly
unlikely.
Warnings and precautions as listed on the product literature are adequate to
ensure safety to users of the product: Avoid accidental self-injection. In case of accidental self-injection, seek
medical advice immediately and show the package leaflet or label to the
doctor.
 Avoid contact with skin and eyes. In case of contact with skin or eyes,
rinse immediately with fresh water.
Ecotoxicity
The applicant provided a Phase I environmental risk assessment in compliance
with the relevant guideline which showed that no further assessment is required.
The assessment concluded that apometic is intended for non- food animals, for
VMD/L4/GAT/014/C
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Apometic 10 mg/ml Solution for Injection
Forum Products Limited
Application for National Procedure
Publicly Available Assessment Report
individual treatment only and, as such, is unlikely to pose a risk to the
environment. 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
Apomorphine is a synthetic derivative of morphine and a dopaminergic agonist,
which primarily affects the hypothalamic region of the brain. It induces emesis by
stimulating post-synaptic dopamine (D2) receptors in the chemoreceptor trigger
zone (CTZ) in the brain.
Apomorphine does not have analgesic, opiate or addictive properties however
when given at higher doses it can act to suppress vomiting by stimulating the µ
receptors in the vomiting centre of the brain. Transient effects of apomorphine
include reduction of blood pressure and body temperature, accompanied by an
increase in heart rate.
In the conscious dog apomorphine causes gastric relaxation and vomiting, which
is blocked by administration of dopamine antagonists such as domeperidone
and haloperidol. It has also been shown that apomorphine is more effective
following subcutaneous administration than intramuscular administration. This is
due to the location of the CTZ outside the blood-brain barrier whereas the
vomiting centre is within the brain. The apomorphine acts initially at the CTZ to
induce vomiting before crossing the blood-brain barrier and inhibiting vomiting by
acting on µ-receptors in the vomiting centre. This creates a self limiting effect
which can be reduced by blocking the µ-receptors with naloxone resulting in a
prolonged effect of apomorphine.
Pharmacokinetics
Following subcutaneous administration apomorphine hydrochloride is rapidly
absorbed and peak plasma concentrations are reached within 20-25 minutes.
Concentrations sufficient to induce emesis in dogs are reached within 10
minutes following injection.
Apomorphine is lipophilic and is extensively distributed to tissues. After injection
it rapidly diffuses across the blood-brain barrier. Apomorphine is extensively
metabolised in the liver by oxidation into non-active metabolites.
The metabolites of apomorphine, and a little unchanged apomorphine (<2%), is
excreted via the urine. Apomorphine has a short elimination half life in dogs of
30 – 64 minutes.
VMD/L4/GAT/014/C
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Apometic 10 mg/ml Solution for Injection
Forum Products Limited
Application for National Procedure
Publicly Available Assessment Report
Tolerance in the Target Species of Animals
The applicant has not conducted any controlled target animal tolerance studies
but has instead supplied a summary of the literature. The product literature
reflects the type and incidence of adverse effects which might be expected.
One study cited by the applicant looked at the tolerance of apomorphine in dogs
and measured several physiological parameters. They found apomorphine
results in decreased temperature and blood pressure but an increase in the
heart rate. Emesis occurred in 71% of the dogs.
No adverse effects have been reported for any of the excipients used in this
product and only two cases of suspected adverse reaction have been reported
for apomorphine HCl. In both cases a suspected lack of expected efficacy is
recorded. Dogs were injected with a dose of 0.1 mg/ kg apomorphine following
suspected poisoning. In one case the dog lost consciousness but vomited after
awakening 30 minutes later, whilst the other dog did not vomit so they used soda
crystals which triggered emesis before the animal showed signs of sedation 30
minutes later.
The required warnings and precautions are listed on the SPC and product
literature.
IV.B
Clinical Studies
Laboratory Trials
The applicant has not conducted any clinical studies but has instead provided
evidence from literature to support the proposed dose, route of administration
and to demonstrate the efficacy of apomorphine. Therefore a full set of
supporting efficacy data are not available for this product, as this is a Limited
Marketing Authorisation this is acceptable.
Evidence to support the route of administration was provided. A study has been
cited, in which it was determined subcutaneous administration was more
effective at producing emesis than intramuscular administration. Therefore this
product is to be administered via subcutaneous injection.
Similarly several studies have been included that look at the dose required to
produce an emetic effect. One such study found a dose of 0.03 mg/kg
subcutaneously was sufficient to produce vomiting in the conscious dog, whilst
another study used a dose of 0.1 mg/kg to trigger emesis in Beagles. A third
study found that emesis was dose dependent after injecting subcutaneously 0.04
mg/kg up to 0.1 mg/kg, however in all cases vomiting occurred. In further studies
apomorphine injected at higher doses of 0.3 mg/kg which resulted in vomiting
and no self-limiting effects were observed. Therefore the applicant determined
that 0.1 mg/kg as used in the other studies is a conservative amount, and the
chance of overdosing starts at doses greater than 0.3 mg/kg, so has decided a
dose of 0.2 mg/kg should be used to induce emesis.
VMD/L4/GAT/014/C
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Apometic 10 mg/ml Solution for Injection
Forum Products Limited
Application for National Procedure
Publicly Available Assessment Report
No data were presented for dose conformation or field studies. This is
acceptable for a Limited Marketing Authorisation given the long period of use
and known pharmacology of the active substance.
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.
VMD/L4/GAT/014/C
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Apometic 10 mg/ml Solution for Injection
Forum Products Limited
Application for National Procedure
Publicly Available Assessment Report
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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