TULATHROMYCIN Bioveta 100 mg/ml solution for injection for cattle, pigs and sheep

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QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml contains:

Active substance:

Tulathromycin 100 mg

Excipients:

Qualitative composition of excipients and other constituents	Quantitative composition if that information is essential for proper administration of the veterinary medicinal product
Monothioglycerol	5.0 mg
Propylene glycol
Citric acid monohydrate
Hydrochloric acid, concentrated (for pH adjustment)
Sodium hydroxide (for pH adjustment)
Water for injections

Clear, colourless to slightly yellow solution.

CLINICAL INFORMATION

Target species

Cattle, pigs, sheep.

Indications for use for each target species

Cattle

Treatment and metaphylaxis of bovine respiratory disease (BRD) associated with Mannheimia haemolytica, Pasteurella multocida, Histophilus somni and Mycoplasma bovis. The presence of the disease in the group must be established before the veterinary medicinal product is used.

Treatment of infectious bovine keratoconjunctivitis (IBK) associated with Moraxella bovis.

Pigs

Treatment and metaphylaxis of swine respiratory disease (SRD) associated with Actinobacillus pleuropneumoniae, Pasteurella multocida, Mycoplasma hyopneumoniae, Glaesserella (Haemophilus) parasuis and Bordetella bronchiseptica. The presence of the disease in the group must be established before the veterinary medicinal product is used. The veterinary medicinal product should only be used if pigs are expected to develop the disease within 2–3 days.

Sheep

Treatment of the early stages of infectious pododermatitis (foot rot) associated with virulent Dichelobacter nodosus requiring systemic treatment.

Contraindications

Do not use in cases of hypersensitivity to macrolide antibiotics or to any of the excipients.

Special warnings

Cross-resistance has been shown between tulathromycin and other macrolides. Use of the tulathromycin should be carefully considered when susceptibility testing has shown resistance to other macrolides, lincosamides and group B streptogramins because its effectiveness may be reduced (cross resistance).

Sheep:

The efficacy of antimicrobial treatment of foot rot might be reduced by other factors, such as wet environmental conditions, as well as inappropriate farm management. Treatment of foot rot should therefore be undertaken along with other flock management tools, for example providing dry environment.

Antibiotic treatment of benign foot rot is not considered appropriate. Tulathromycin showed limited efficacy in sheep with severe clinical signs or chronic foot rot and should therefore only be given at an early stage of foot rot.

Special precautions for use

Special precautions for safe use in the target species:

Use of the veterinary medicinal product should be based on identification and susceptibility testing of the target pathogen(s). If this is not possible, therapy should be based on epidemiological information and knowledge of susceptibility of the target pathogens at farm level, or at local/regional level.

Use of the veterinary medicinal product should be in accordance with official, national and regional antimicrobial policies.

Use of the veterinary medicinal product deviating from the instructions given in the summary of product characteristics (SPC) may increase the prevalence of bacteria resistant to tulathromycin and may decrease the effectiveness of treatment with other macrolides, lincosamides and group B streptogramins, due to the potential for cross resistance.

An antibiotic with a lower risk of antimicrobial resistance selection (lower AMEG category) should be used for first line treatment where susceptibility testing suggests the likely efficacy of this approach.

If a hypersensitivity reaction occurs appropriate treatment should be administered without delay.

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

Tulathromycin is irritating to eyes. In case of accidental eye exposure, flush the eyes immediately with clean water.

Tulathromycin may cause sensitisation by skin contact resulting in e.g. reddening of the skin (erythema) and/or dermatitis. In case of accidental spillage onto skin, wash the skin immediately with soap and water.

In case of accidental self-injection, seek medical advice immediately and show the package leaflet or the label to the physician.

If there is suspicion of a hypersensitivity reaction following accidental exposure (recognised by e.g. itching, difficulty in breathing, hives, swelling on the face, nausea, vomitus) appropriate treatment should be administered. Seek medical advice immediately and show the package leaflet or the label to the physician.

Wash hands after use.

Special precautions for the protection of the environment:

Not applicable.

Adverse events

Cattle:

Very common (>1 animal / 10 animals treated):

injection site pain, injection site swelling1,2

Cattle and pigs:

Very common (>1 animal / 10 animals treated):

injection site reaction3, injection site oedema, injection site fibrosis, injection site haemorrhage2

Sheep:

Very common (>1 animal / 10 animals treated):

discomfort4

¹ After subcutaneous administration.

² These signs can persist for up to 30 days.

³ Reversible changes of congestion.

⁴ Transient, resolving within a few minutes: head shaking, rubbing injection site, backing away.

Reporting adverse events is important. It allows continuous safety monitoring of a veterinary medicinal product. Reports should be sent, preferably via a veterinarian, to either the marketing authorisation holder or its local representative or the national competent authority via the national reporting system. See the package leaflet for respective contact details.

Use during pregnancy, lactation or lay

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

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

Laboratory studies in rats and rabbits have not produced any evidence of teratogenic, foetotoxic or maternotoxic effects.

Interaction with other medicinal products and other forms of interaction

None known.

Administration routes and dosage

Cattle

Subcutaneous use.

A single subcutaneous injection of 2.5 mg tulathromycin/kg bodyweight (equivalent to 1 ml/40 kg bodyweight). For treatment of cattle over 300 kg bodyweight, divide the dose so that no more than 7.5 ml are injected at one site.

Pigs

Intramuscular use.

A single intramuscular injection of 2.5 mg tulathromycin/kg bodyweight (equivalent to 1 ml/40 kg bodyweight) in the neck.

For treatment of pigs over 80 kg bodyweight, divide the dose so that no more than 2 ml are injected at one site.

For any respiratory disease, it is recommended to treat animals in the early stages of the disease and to evaluate the response to treatment within 48 hours after injection. If clinical signs of respiratory disease persist or increase, or if relapse occurs, treatment should be changed, using another antibiotic, and continued until clinical signs have resolved.

Sheep

Intramuscular use.

A single intramuscular injection of 2.5 mg tulathromycin/kg body weight (equivalent to 1 ml/40 kg body weight) in the neck.

To ensure correct dosage bodyweight should be determined as accurately as possible to avoid underdosing. For multiple vial entry, an aspirating needle or multi-dose syringe is recommended to avoid excessive broaching of the stopper.

The rubber stopper may be punctured up to 30 times.

Symptoms of overdose (and where applicable, emergency procedures and antidotes)

In cattle at dosages of three, five or ten times the recommended dose, transient signs attributed to injection site discomfort were observed and included restlessness, head-shaking, pawing the ground, and brief decrease in feed intake. Mild myocardial degeneration has been observed in cattle receiving five to six times the recommended dose.

In young pigs weighing approximately 10 kg given three or five times the therapeutic dose transient signs attributed to injection site discomfort were observed and included excessive vocalisation and restlessness. Lameness was also observed when the hind leg was used as the injection site.

In lambs (approx. 6 weeks old), at dosages of three or five times the recommended dose, transient signs attributed to injection site discomfort were observed, and included walking backwards, head shaking, rubbing the injection site, lying down and getting up, bleating.

Special restrictions for use and special conditions for use, including restrictions on the use of antimicrobial and antiparasitic veterinary medicinal products in order to limit the risk of development of resistance

Not applicable.

Withdrawal periods

Cattle: Meat and offal: 22 days.

Pigs: Meat and offal: 13 days.

Sheep: Meat and offal: 16 days.

Not authorised for use in animals producing milk for human consumption.

Do not use in pregnant animals which are intended to produce milk for human consumption within 2 months of expected parturition.

PHARMACOLOGICAL INFORMATION

ATCvet code: QJ01FA94

Pharmacodynamics

Tulathromycin is a semi-synthetic macrolide antimicrobial agent, which originates from a fermentation veterinary medicinal product. It differs from many other macrolides in that it has a long duration of action that is, in part, due to its three amine groups; therefore, it has been given the chemical subclass designation of triamilide.

Macrolides are bacteriostatic acting antibiotics and inhibit essential protein biosynthesis by virtue of their selective binding to bacterial ribosomal RNA. They act by stimulating the dissociation of peptidyl-tRNA from the ribosome during the translocation process.

Tulathromycin possesses in vitro activity against Mannheimia haemolytica, Pasteurella multocida, Histophilus somni and Mycoplasma bovis, and Actinobacillus pleuropneumoniae, Pasteurella multocida, Mycoplasma hyopneumoniae, Glaesserella (Haemophilus) parasuis and Bordetella bronchiseptica, the bacterial pathogens most commonly associated with bovine and swine respiratory disease respectively. Increased minimum inhibitory concentration (MIC) values have been found in some isolates of Histophilus somni, Actinobacillus pleuropneumoniae and Pasteurella multocida (cattle). In vitro activity against Dichelobacter nodosus (vir), the bacterial pathogen most commonly associated with infectious pododermatitis (foot rot) in sheep has been demonstrated.

Tulathromycin also possesses in vitro activity against Moraxella bovis, the bacterial pathogen most commonly associated with infectious bovine keratoconjunctivitis (IBK).

The Clinical and Laboratory Standards Institute CLSI has set the clinical breakpoints for tulathromycin against M. haemolytica, P. multocida, and H. somni of bovine respiratory origin and P. multocida and B. bronchiseptica of swine respiratory origin as ≤16 μg/ml susceptible and ≥64 μg/ml resistant. For A. pleuropneumoniae of swine respiratory origin the susceptible breakpoint is set at ≤64 μg/ml. CLSI has also published clinical breakpoints for tulathromycin based on a disk diffusion method (CLSI document VET08, 4th ed, 2018). No clinical breakpoints are available for Glaesserella (Haemophilus) parasuis. Neither EUCAST nor CLSI have developed standard methods for testing antibacterial agents against veterinary Mycoplasma species and thus no interpretative criteria have been set.

Resistance to macrolides can develop by mutations in genes encoding ribosomal RNA (rRNA) or some ribosomal proteins; by enzymatic modification (methylation) of the 23S rRNA target site, generally giving rise to cross-resistance with lincosamides and group B streptogramins (MLS_B resistance); by enzymatic inactivation; or by macrolide efflux. MLS_B resistance may be constitutive or inducible. Resistance may be chromosomal or plasmid-encoded and may be transferable if associated with transposons, plasmids, integrative and conjugative elements. Additionally, the genomic plasticity of Mycoplasma is enhanced by the horizontal transfer of large chromosomal fragments.

In addition to its antimicrobial properties, tulathromycin demonstrates immune-modulating and antiinflammatory actions in experimental studies. In both bovine and porcine polymorphonuclear cells (PMNs; neutrophils), tulathromycin promotes apoptosis (programmed cell death) and the clearance of apoptotic cells by macrophages. It lowers the production of the pro-inflammatory mediators leukotriene B4 and CXCL-8 and induces the production of anti-inflammatory and pro-resolving lipid lipoxin A4.

Pharmacokinetics

In cattle, the pharmacokinetic profile of tulathromycin when administered as a single subcutaneous dose of 2.5 mg/kg bodyweight, was characterised by rapid and extensive absorption followed by high distribution and slow elimination. The maximum concentration (C_max) in plasma was approximately 0.5 μg/ml; this was achieved approximately 30 minutes post-dosing (T_max). Tulathromycin concentrations in lung homogenate were considerably higher than those in plasma. There is strong evidence of substantial accumulation of tulathromycin in neutrophils and alveolar macrophages. However, the in vivo concentration of tulathromycin at the infection site of the lung is not known. Peak concentrations were followed by a slow decline in systemic exposure with an apparent elimination half-life (t _1/2) of 90 hours in plasma. Plasma protein binding was low, approximately 40%. The volume of distribution at steady-state (V_ss) determined after intravenous administration was 11 l/kg. The bioavailability of tulathromycin after subcutaneous administration in cattle was approximately 90%.

In pigs, the pharmacokinetic profile of tulathromycin when administered as a single intramuscular dose of 2.5 mg/kg bodyweight, was also characterised by rapid and extensive absorption followed by high distribution and slow elimination. The maximum concentration (C_max) in plasma was approximately 0.6 μg/ml; this was achieved approximately 30 minutes post-dosing (T_max). Tulathromycin concentrations in lung homogenate were considerably higher than those in plasma. There is strong evidence of substantial accumulation of tulathromycin in neutrophils and alveolar macrophages. However, the in vivo concentration of tulathromycin at the infection site of the lung is not known. Peak concentrations were followed by a slow decline in systemic exposure with an apparent elimination half-life (t_1/2) of approximately 91 hours in plasma. Plasma protein binding was low, approximately 40%. The volume of distribution at steady-state (V_ss) determined after intravenous administration was 13.2 l/kg. The bioavailability of tulathromycin after intramuscular administration in pigs was approximately 88%.

In sheep, the pharmacokinetic profile of tulathromycin, when administered as a single intramuscular dose of 2.5 mg/kg bodyweight, achieved a maximum plasma concentration (C_max) of 1.19 μg/ml in approximately 15 minutes (T_max) post-dosing and had an elimination half-life (t_1/2) of 69.7 hours. Plasma protein binding was approximately 60-75%. Following intravenous dosing the volume of distribution at steady-state (V_ss) was 31.7 l/kg. The bioavailability of tulathromycin after intramuscular administration in sheep was 100%.

PHARMACEUTICAL PARTICULARS

Major incompatibilities

In the absence of compatibility studies, this veterinary medicinal product must not be mixed with other veterinary medicinal products.

Shelf life

Shelf life of the veterinary medicinal product as packaged for sale: 2 years.

Shelf life after first opening the immediate packaging: 28 days.

Special precautions for storage

This veterinary medicinal product does not require any special storage conditions.

Nature and composition of immediate packaging

Cardboard box containing a type II clear glass vial with 50 ml or 100 ml of the veterinary medicinal product closed with a bromobutyl rubber stopper with a flip-off aluminium cap.

Not all pack sizes may be marketed.

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

Medicines should not be disposed of via wastewater or household waste.

Use take-back schemes for the disposal of any unused veterinary medicinal product or waste materials derived thereof in accordance with local requirements and with any national collection systems applicable to the veterinary medicinal product concerned.