Alizin 30 mg/ml Solution for Injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1 ml contains:
- active substance
aglepristone…………………………………..  30 mg

3. PHARMACEUTICAL FORM

Solution for injection.
Clear yellow oily solution.

4. CLINICAL PARTICULARS

4.1 Target species

Dogs (bitches).

4.2 Indication for use,specifying the target species

Pregnant bitches: induction of abortion up to 45 days after mating.

4.3 Contra-indications

Do not use in dogs with impaired hepatic or renal function, in diabetic animals or in dogs in poor health.

Do not use in dogs with eithermanifest or latent hypoadrenocorticism (Addison’s disease) or in dogs with agenetic predisposition to hypoadrenocorticism.

Do not use in dogs with known hypersensitivity to aglepristone or the veterinary  medicinal product excipient.

4.4 Special warnings foreach target species

Rare cases of lack of efficacy(>0.01 % to < 0.1%) have been reported as part of the pharmacovigilance survey. To reduce the possibility of lack of expected efficacy, avoid the useof Alizin until after the end of oestrus and avoid new mating before the end of oestrus.

In bitches confirmed pregnant, apartial abortion was observed in 5%  of cases in field trials. A thoroughclinical examination is always recommended in order to confirm that the uteruscontent is fully evacuated. Ideally, the examination should be conducted usingultrasound. This examination should be performed 10 days after treatment and atleast 30 days after mating.

In case of partial abortion orno abortion, repeat treatment may be recommended 10 days after treatment,between day 30 and day 45 after mating. Surgery should also be considered..

4.5 Special precautionsfor use

(i) Special precautions for use in animals

In the absence of availabledata, the veterinary medicinal product should be used with caution in dogs withchronic obstructive-airway disease and/or cardiovascular disease, particularlybacterial endocarditis.

Fatalities have been reportedsubsequent to off-label use in seriously ill bitches with uterine infections. Acausal association is difficult to determine but is unlikely.

In up to 50 % of bitches, mating may not be followed by pregnancy. The possibility that a bitch may therefore betreated unnecessarily should be taken into account in evaluating the product risk-benefit ratio.

Bitches that remain pregnant despite treatment should be monitored, as viabililty of the puppies may be compromised.

Possible long-term effects of treatment have not been studied.

Owners should be advised to consult their veterinary surgeon if their dog shows the following signs after treatment with the veterinary medicinal product:
- purulent or haemorragic vaginal discharge
- prolonged vaginal discharge lasting over 3 weeks.

(ii) Special precautions to betaken by the person administering the veterinary medicinal product to animals

Nor-steroids are used in humans to induce abortion. Accidental injection may be a particular hazard to womenwho are pregnant, intending to become pregnant or whose pregnancy status isunknown. Care should be taken by the veterinary surgeon when handling theproduct and the person restraining the dog to avoid accidental injection. Pregnant women should administer the product with caution. This is an oil-based product that may cause prolonged local reactions at the site of injection. In case of accidental injection, seek urgent medical advice and show the doctor thiswarning.

Women of child-bearing age should avoid contact with the veterinary medicinal product or wear disposable plastic gloves when administering the veterinary medicinal product.

4.6 Adverse reactions(frequency and seriousness)

In bitches treated after 20 daysof gestation, abortion is accompanied by the physiological signs ofparturition: fetal expulsion, vaginal discharge, reduced appetite, restlessnessand mammary congestion. In field trials, 3.4 % of dogs suffered from uterineinfections. After induced abortion with the veterinary medicinal product, anearly return to oestrus is frequently observed (oestrus   oestrusinterval shortened by 1 to 3 months).

Side effects such as anorexia(25 %), excitation (23 %), depression (21 %), vomiting (2 %) and diarrhoea (13%) have been reported from field trials.

In field trials, theadministration of the veterinary medicinal product produced pain during andshortly after injection in 17 % of dogs and a local inflammatory reaction atthe injection site in 23 % of dogs.  The size and intensity of thisreaction depended on the volume of the veterinary medicinal product which wasadministered. Oedema, skin thickening, local lymph-node enlargement andulceration may occur. All local reactions are reversible and will usuallydisappear within 28 days after injection.
In field trials, administration of the veterinary medicinal product inducedhaematological/biochemical changes in 4.5 % of dogs. These changes were alwaystransient and reversible. The modified haematological parameters were asfollows: neutrophilia, neutropaenia, thrombocytosis, haematocrit variation,lymphocytosis, lymphopaenia.
The modified (elevated) biochemical parameters were as follows: urea,creatinine, chloride, potassium, sodium, ALT, ALP, AST.
In rare cases (frequency > 1/10000 and < 1/1000), a hypersensitivityreaction has been/can be observed.

4.7 Use during pregnancy,lactation or lay

Do not administer to pregnantbitches unless it is desirable to terminate the pregnancy.

4.8 Interaction withother medicinal products and other forms of interaction

In the absence of availabledata, a risk of drug interaction between aglepristone and ketoconazole,itraconazole and erythromycin may exist.

As aglepristone is ananti-glucocorticoid, it might reduce the effect of glucocorticoid treatment.

Possible interactions with othermedicaments have not been studied.

4.9 Overdose (symptoms,emergency procedures, antidotes), if necessary

The administration of 30 mg/kg,i.e. 3 times the recommended dose, in bitches showed no adverse effects, exceptlocal inflammatory reactions, related to the larger volumes injected.

4.10 Withdrawal period

Not applicable.

PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group:antiprogestogen.

5.1 Pharmacodynamicproperties

Aglepristone is a syntheticsteroid counteracting the effect of progesterone by competing with thishormone  at the level of  the uterine receptors, resulting in abortion(or resorption)  within 7 days after administration.

Aglepristone does not modifyprogesterone, prostaglandins, oxytocin or cortisol plasma concentration within 24 hours after its administration but it induces a discharge of prolactin within 12 hours.

In vitro, the affinity ofaglepristone for the progesterone receptors in the uterus of the dog is 3 times higher than that of progesterone.

The relative binding affinity of aglepristone to glucocorticoid receptors is similar to that of dexamethasone but aglepristone has antagonistic properties.

5.2 Pharmacokinetic particulars

After 2 injections of 10mg/kg/day at a 24-hour interval, the maximal concentration (about 280 ng/ml) is reached after 2.5 days. The mean residence time is around 6 days: this period includes the mean absorption time from the injection site.

After administration of a 10mg/kg radio-labelled dose, the excretion of radioactivity is very slow. Only 60% of the administered dose is excreted during the first 10 days and around 80 %over 24 days.

Excretion is essentially via thefaeces (around 90 %).

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

- Anhydrous ethanol
- Refined arachis oil.

6.2 Incompatibilities

None known.
Do not mix with other veterinary medical products.

6.3 Shelf life

Shelf life of the veterinary medicinal product as packaged for sale: 3 years.
Shelf life after first opening the immediate packaging: 28 days.

6.4. Special precautionsfor storage

Keep the vial in the outer carton in order to protect from light.

Should any apparent growth or discoloration occur, the product should be discarded.

6.5 Nature andcomposition of immediate packaging

Vials (glass, type II) of 5 ml,10 ml or 30 ml for injectable preparations with bromobutyl stoppers and aluminium caps.

Presentations:
- box of 1 vial of 10 ml, 
-

6.6 Special precautions for the disposal of unused veterinary medicinal product or waste 

materials derived fromthe use of such products

Any unused product or wwaste material hould be disposed of in accordance with national requirements.