SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE VETERINARY MEDICINAL PRODUCT

Milbotyl 300 mg/ml solution for injection

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One ml contains:

Active substance:

Tilmicosin 300mg

Excipients:

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection.

Clear yellow solution.

4. CLINICAL PARTICULARS

4.1 Target species

Cattle and sheep

4.2 Indications for use, specifying the target species

Cattle

For the treatment of bovine respiratory disease associated with Mannheimia haemolyticaandPasteurella multocida.

For the treatment of interdigital necrobacillosis.

Sheep

For the treatment of respiratory tract infections caused by Mannheimia haemolyticaandPasteurella multocida.

Treatment of foot rot in sheep caused by Dichelobacter nodosus and Fusobacterium necrophorum.

Treatment of acute ovine mastitis caused by Staphylococcus aureus and Mycoplasma agalactiae.

4.3 Contraindications

Do not administer intravenously.

Do not administer intramuscularly.

Do not administer to lambs weighing less than 15 kg.

Do not administer to primates.

Do not administer to pigs.

Do not administer to horses and donkeys.

Do not administer to goats.

Do not use in case of hypersensitivity to the active substance or to any of the excipients.

4.4 Special warnings <for each target species>

Sheep

The clinical trials did not demonstrate a bacteriological cure in sheep with acute mastitis caused by Staphylococcus aureus and Mycoplasma agalactiae.

Do not administer to lambs weighing less than 15 kg, since there is a real risk of overdosage toxicity. Accurate weighing of lambs is important to avoid overdosage. The use of a 2 ml or smaller syringe will improve accurate dosing.

4.5 Special precautions for use

Special precautions for use in animals

Official, national and regional antimicrobial policies should be taken into account when the product is used.

To avoid self-injection do not use automatic injection equipment.

Wherever possible, the use of the product should be based on susceptibility testing.

Special precautions to be taken by the person administering the veterinary medicinal product to animals

INJECTION OF TILMICOSIN IN HUMANS CAN BE FATAL – EXERCISE EXTREME CAUTION TO AVOID ACCIDENTAL SELF-INJECTION AND FOLLOW THE ADMINISTRATION INSTRUCTIONS AND THE GUIDANCE BELOW, PRECISELY

• This product should only be administered by a veterinary surgeon.

• Never carry a syringe loaded with MILBOTYL 300 mg/ml SOLUTION FOR INJECTION with the needle attached. The needle should be connected to the syringe only when filling the syringe or administering the injection. Keep the syringe and needle separate at all other times.

• Do not use automatic injection equipment.

• Ensure that animals are properly restrained, including those in the vicinity.

• Do not work alone when using MILBOTYL 300 mg/ml SOLUTION FOR INJECTION.

• In case of human injection SEEK IMMEDIATE MEDICAL ATTENTION and take the vial or the package leaflet with you. Apply a cold pack (not ice directly) to the injection site.

Additional operator safety warnings:

NOTE TO THE PHYSICIAN

INJECTION OF TILMICOSIN IN HUMANS HAS BEEN ASSOCIATED WITH FATALITIES.

The cardiovascular system is the target of toxicity, and this toxicity may be due to calcium channel blockade. Administration of intravenous calcium chloride should only be considered if there is positive confirmation of exposure to tilmicosin.

In dog studies, tilmicosin induced a negative inotropic effect with consequent tachycardia, and a reduction in systemic arterial blood pressure and arterial pulse pressure.

DO NOT GIVE ADRENALINOR BETA-ADRENERGIC ANTAGONISTS SUCH AS PROPRANOLOL.

In pigs, tilmicosin-induced lethality is potentiated by adrenalin.

In dogs, treatment with intravenous calcium chloride showed a positive effect on the left ventricular inotropic state and some improvements in vascular blood pressure and tachycardia.

Pre-clinical data and an isolated clinical report suggest that calcium chloride infusion may help to reverse tilmicosin induced changes in blood pressure and heart rate in humans.

Administration ofdobutamine should also be considered due to its positive inotropic effects although it does not influence tachycardia.

As tilmicosin persists in tissues for several days, the cardiovascular system should be closely monitored and supportive treatment provided.

Physicians treating patients exposed to this compound are advised to discuss clinical management with the National Poison Information Service on: 018379964 (IE) or 0844 892 0111 (UK).

4.6 Adverse reactions (frequency and seriousness)

Occasionally, a soft diffuse swelling may occur at the injection site but this disappears within five to eight days. In rare cases recumbency, incoordination and convulsions have been observed.

Deaths of cattle have been observed following a single intravenous dose of 5 mg/kg body weight, and following the subcutaneous injection of doses of 150 mg/kg body weight at 72 hour intervals. In pigs, intramuscular injection at 20 mg/kg body weight has caused deaths. Sheep have died following a single intravenous injection of 7.5mg/kg body weight.

4.7 Use during pregnancy, lactation or lay

The safety of the veterinary medicinal product has not been established during pregnancy.

Use only according to the benefit/risk assessment by the responsible veterinarian.

4.8 Interaction with other medicinal products and other forms of interaction

Interactions between macrolides and ionophores have been observed in some species.

4.9 Amounts to be administered and administration route

For subcutaneous injection only.

Use 10 mg tilmicosin per kg body weight (corresponding to 1 ml of Milbotyl per 30 kg bodyweight).

Cattle:

Method of administration:

Withdraw the required dose from the vial and remove the syringe from the needle, leaving the needle in the vial. When a group of animals has to be treated, leave the needle in the vial to remove the subsequent doses. Restrain the animal and insert a separate needle subcutaneously at the injection site, preferably in a skinfold over the rib cage behind the shoulder. Attach the syringe to the needle and inject into the base of the skinfold. Do not inject more than 20 ml per injection site.

Sheep:

Method of administration:

Accurate weighing of lambs is important to avoid overdosage.The use of a 2ml or smaller syringe will improve accurate dosing.

Withdraw the required dose from the vial and remove the syringe from the needle, leaving the needle in the vial. Restrain the sheep whilst leaning over the animal and insert a separate needle subcutaneously into the injection site, which should be in a skinfold over the rib cage behind the shoulder. Attach the syringe to the needle and inject into the base of the skinfold. Do not inject more than 2 ml per injection site.

If no improvement is noted within 48 hours, the diagnosis should be confirmed.

Avoid introduction of contamination into vial during use. The vial should be inspected visually for any foreign particulate matter and/or abnormal physical appearance. In the event of either being observed, discard the vial.

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

In cattlesubcutaneous injections of 10, 30 and 50 mg/kg bodyweight, repeated three times with a 72 hours interval, did not cause death. As expected, oedema developed at the site of injection. The only lesion observed at autopsy was a necrosis of the myocardium in the group treated with 50 mg/kg bodyweight.

Doses of 150 mg/kg bodyweight, administered subcutaneously with an interval of 72 hours caused death. Oedema at the site of injection was observed and at autopsy a light necrosis of the myocardium was the only lesion determined. Other symptoms observed were: difficulty in moving, reduced appetite and tachycardia.

In sheepsingle injections (approximately 30 mg/kg body weight) may cause a slight increase of the rate of respiration. Higher doses (150 mg/kg body weight) caused ataxia, lethargy and the inability to raise the head.

Deaths occurred after one intravenous injection of 5 mg/kg body weight in cattle and

7.5 mg/kg body weight in sheep.

4.11 Withdrawal period(s)

Cattle;

Meat and offal: 70 days.

Milk: 36 days.

If the product is to be administered to cows during the dry period or to pregnant dairy heifers (in accordance with section 4.7 above), milk should not be used for human consumption until 36 days after calving.

Sheep;

Meat and offal: 42 days.

Milk: 18 days.

If the product is to be administered to ewes during the dry period or to pregnant ewes (in accordance with section 4.7 above), milk should not be used for human consumption until 18 days after lambing.

5. PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic Group: antibacterials for systemic use, macrolides.

ATC vet code: QJ01FA91.

5.1 Pharmacodynamic properties

Tilmicosin is a mainly bactericidal semi-synthetic antibiotic of the macrolide group. It is believed to affect protein synthesis. It has bacteriostatic action but at high concentrations it may be bactericidal.

This antibacterial activity is predominantly against Gram-positivemicroorganism with activity against certain Gram-negative ones and Mycoplasmaof a bovine and ovine origin. In particular its activity has been demonstrated against the following micro-organism:

Mannheimia, Pasteurella, Actinomyces (Corynebacterium), Fusobacterium, Dichelobacter, Staphylococcus, and.Mycoplasmaorganisms of a bovine and ovine origin.

Minimum inhibition concentrations measured in recently (2009-2012) isolated European field strains, derived from respiratory bovine disease.

Bacteria spp	MIC (g/ml) range	MIC50 (g/ml)	MIC90 (g/ml)
P. multocida	0.5 - > 64	4	8
M. haemolytica	1 - 64	8	16

The Clinical and Laboratory Standards Institute (CLSI) has set the interpretive criteria for tilmicosin against M. haemolyica of bovine origin and specifically for bovine respiratory disease, as ≤8µg/ml = susceptible, 16 µg/ml = intermediate and ≥ 32 µg/ml = resistant. The CLSI at the present time have no interpretive criteria for P. multocida of bovine origin, however they have interpretive criteria for P. multocida of swine origin, specifically swine respiratory disease, as ≤16 µg/ml = susceptible and ≥ 32 µg/ml = resistant.

Scientific evidence suggests that macrolides act synergistically with the host immune system. Macrolides appear to enhance phagocyte killing of bacteria.

Following oral or parenteral administration of tilmicosin the main target organ for toxicity is the heart. The primary cardiac effects are increased heart rate (tachycardia) and decreased contractility (negative inotrophy). Cardiovascular toxicity may be due to calcium channel blockade.

In dogs, CaCl₂ treatment showed a positive effect on the left ventricular inotrophic state after tilmicosin administration and some changes in vascular blood pressure and heart rate.

Dobutamine partially offset the negative inotrophic effects induced by tilmicosin in dogs. Beta adrenergic antagonists such as propanolol exacerbated the negative inotrophy of tilmicosin in dogs.

In pigs, intramuscular injection of 10 mg tilmicosin/kg body weight caused increased respiration, emesis and convulsions; 20 mg/kg body weight resulted in mortality in 3 of 4 pigs, and 30 mg/kg body weight caused the death of all 4 pigs tested. Intravenous injection of 4.5 to 5.6 mg tilmicosin/kg body weight followed by intravenous injection of 1 ml epinephrine (1/1000) 2 to 6 times resulted in death of all 6 injected pigs. Pigs given 4.5 to 5.6 mg tilmicosin/kg body weight intravenously with no epinephrine all survived. These results suggest that intravenous epinephrine may be contraindicated.

Cross resistance between tilmicosin and other macrolides and lincomycin has been observed.

5.2 Pharmacokinetic particulars

Absorption: Several studies have been conducted. The results show that, when administered as recommended to calves and sheep by subcutaneous injection over the dorso-lateral chest, the main parameters are:

	Dose rate	Tmax	Cmax
Cattle: Neonatal calves Feedlot cattle	10 mg/kg body weight 10 mg/kg body weight	1 hour 1 hour	1.55 µg/ml 0.97 µg/ml
Sheep 40 kg animals 28-50 kg animals	10 mg/kg body weight 10 mg/kg body weight	8 hours 8 hours	0.44 µg/ml 1.18 µg/ml

Distribution: Following subcutaneous injection, tilmicosin is distributed throughout the body, but especially high levels are found in the lung.

Biotransformation: Several metabolites are formed, the predominant one being identified as T1 (N-demethyl tilmicosin). However the bulk of the tilmicosin is excreted unchanged.

Elimination: Following subcutaneous injection, tilmicosin is excreted mainly via the bile into the faeces, but a small proportion is excreted via the urine. The half-life following subcutaneous injection in cattle is 2-3 days.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Propylene Glycol.

Phosphoric acid (for pH adjustment)

Water for injections.

6.2 Incompatibilities

In the absence of compatibility studies, this veterinary medicinal product must not be mixed with other veterinary medicinal 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 precautions for storage

Do not store above 30C.

Protect from direct sunlight.

6.5 Nature and composition of immediate packaging

50 ml and 100 ml pack: Amber neutral glass (Type II) vial, closed, with grey bromobutyl rubber stopper secured with aluminium overseal

250 ml pack: Amber neutral glass (Type II) vial, closed, with pink bromobutyl rubber stopper secured with aluminium overseal

Outer carton of 6, 10 and 12 vials.

Not all pack sizes may be marketed.

6.6 Special precautions for the disposal of unused veterinary medicinal product or waste materials derived from the use of such products

Any unused veterinary medicinal product or waste materials derived from such veterinary medicinal products should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

ChanellePharmaceuticals Manufacturing Ltd.

Loughrea

Co. Galway

Ireland

8. MARKETING AUTHORISATION NUMBER

Vm:08749/4023

9. DATE OF FIRST AUTHORISATION

Date:19 February 2010

10. DATE OF REVISION OF THE TEXT

Date: June 2015

PROHIBITION OF SALE, SUPPLY AND/OR USE

Not applicable.

Approved: 04 June 2015