Zuprevo - summary of medicine characteristics

SUMMARY OF PRODUCT CHARACTERISTICS

• 1. NAME OF THE VETERINARY MEDICINAL PRODUCT

ZUPREVO 40 mg/ml solution for injection for pigs

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One ml contains:

Active substance:

Tildipirosin                    40 mg.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection.

Clear yellowish solution.

4. CLINICAL PARTICULARS4.1 Target species

Pigs

• 4.2 Indications for use, specifying the target species

Treatment and metaphylaxis of swine respiratory disease (SRD) associated with Actinobacillus pleuropneumoniae , Pasteurella multocida, Bordetella bronchiseptica and Haemophilus parasuis sensitive to tildipirosin.

The presence of the disease in the herd should be confirmed before metaphylaxis is implemented.

4.3 Contraindications

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

Do not administer intravenously.

Do not administer simultaneously with other macrolides or lincosamides (see section 4.8)

• 4.4 Special warnings

In line with responsible use principles, metaphylactic use of Zuprevo is only indicated in severe outbreaks of SRD caused by the indicated pathogens. Metaphylaxis implies that clinically healthy animals in close contact with diseased animals are administered the veterinary medicinal product at the same time as the treatment of the clinically diseased animals, to reduce the risk for development of clinical signs.

The efficacy of metaphylactic use of Zuprevo was demonstrated in a placebo controlled multi-centre field study, when outbreak of clinical disease was confirmed (i.e. animals in at least 30% of the pens sharing the same airspace showed clinical signs of SRD, including at least 10% animals per pen within 1 day; or 20% within 2 days or 30% within 3 days). Following metaphylactic use, approximately 86% of the healthy animals remained free of clinical signs of disease (as compared to approximately 65% of animals in the untreated control group).

• 4.5 Special precautions for use

Special precautions for use in animals

Whenever possible, the veterinary medicinal product should only be used based on susceptibility testing. Official, national and regional antimicrobial policies should be taken into account when the veterinary medicinal product is used.

Administer strictly intramuscularly. Special attention should be paid to using the appropriate injection site and to use the appropriate needle size and length (adjusted to the size and weight of animal) according to good veterinary practice.

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

Special caution should be taken to avoid accidental self-injection, as toxicology studies in laboratory animals showed cardiovascular effects after intramuscular administration of tildipirosin. In case of accidental self-injection, seek medical advice immediately and show the package leaflet or the label to the physician.

Do not use in automatically powered syringes which have no additional protection system.

Tildipirosin may cause sensitisation by skin contact. If accidental skin exposure occurs, wash the skin immediately with soap and water. If accidental eye exposure occurs, flush eyes immediately with clean water.

Wash hands after use.

• 4.6 Adverse reactions (frequency and seriousness)

In very rare cases, individual shock reactions with a potentially fatal outcome might occur.

In very rare cases, transient lethargy in piglets has been observed.

In target animal safety studies, administration of the maximum recommended injection volume (5 ml) very commonly caused slight swellings at the injection site that were not painful on palpation.

Swellings persisted for up to 3 days. Pathomorphological injection site reactions resolved completely within 21 days.

During clinical trials, pain on injection and injection site swellings were seen very commonly in treated pigs. These swellings resolved within 1 to 6 days.

The frequency of adverse reactions is defined using the following convention:

• • very common (more than 1 in 10 animals displaying adverse reactions during the course of one treatment)
• • common (more than 1 but less than 10 animals in 100 animals)
• • uncommon (more than 1 but less than 10 animals in 1,000 animals)
• • rare (more than 1 but less than 10 animals in 10,000 animals)
• • very rare (less than 1 animals in 10,000 animals, including isolated reports).

• 4.7 Use during pregnancy and lactation or lay

The safety of the veterinary medicinal product has not been established during pregnancy or lactation. However, there was no evidence for any selective developmental or reproductive effects in any of the laboratory studies.

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

4.8 Interaction with other medicinal products and other forms of interaction

There is cross resistance with other macrolides. Therefore, the product should not be administered with antimicrobials with a similar mode of action such as other macrolides or lincosamides.

• 4.9 Amounts to be administered and administration route

Intramuscular use.

Administer 4 mg tildipirosin/kg body weight (equivalent to 1 ml/10 kg body weight) once only.

The injection volume should not exceed 5 ml per injection site.

The recommended injection site is the location just behind the ear at the highest point of the base of the ear, at the transition from bald to hairy skin.

Injection should be given in a horizontal direction and a 90° angle to the body axis.

Recommended needle size and diameter per production stage

The rubber stopper of the vial may be safely punctured up to 20 times. Otherwise, the use of a multiple-dose syringe is recommended.

To ensure correct dose, body weight should be determined as accurately as possible to avoid underdosing.

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.

4.10 Overdose (symptoms, emergency procedures, antidotes)

In piglets, intramuscular administration of tildipirosin (on three occasions in intervals of 4 days) at 8, 12 and 20 mg/kg body weight (BW) (2, 3 and 5 times the recommended clinical dose), resulted in transient slightly subdued behaviour in one piglet each from the 8 and 12 mg/kg BW group and 2 piglets from the 20 mg/kg BW group following the first or second injection.

Muscle tremors to the hind legs were observed following the first treatment in one pig each from the 12 and 20 mg/kg BW group. At 20 mg/kg body weight one out of eight animals showed transient generalized body tremors with inability to stand after the first administration and the animal showed transient unsteadiness on its feet after the third administration. Another animal developed treatment related shock after the first administration and was euthanized on welfare grounds. Mortality was observed at doses of 25 mg/kg body weight and higher.

• 4.11 Withdrawal period

Meat and offal: 9 days.

5. PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: antibacterials for systemic use, macrolides.

ATCvet code: QJ01FA96.

5.1 Pharmacodynamic properties

Tildipirosin is a 16-membered semi-synthetic macrolide antimicrobial agent. Three amine substituents at the macrocyclic lactone ring result in a tri-basic character of the molecule. The product has a long duration of action; however, the exact clinical effect duration after a single injection is unknown.

Macrolides in general are bacteriostatic antibiotics but for certain pathogens can be bactericidal. They inhibit essential protein biosynthesis by virtue of their selective binding to bacterial ribosomal RNA and act by blocking the prolongation of the peptide chain. The effect is generally time-dependent.

The antimicrobial activity spectrum of tildipirosin includes:

Actinobacillus pleuropneumoniae , Pasteurella multocida , Bordetella bronchiseptica and Haemophilus parasuis, which are the bacterial pathogens most commonly associated with swine respiratory disease (SRD).

In vitro, the effect of tildipirosin is bacteriostatic against Pasteurella multocida and B. bronchiseptica , and bactericidal for A. pleuropneumoniae and H. parasuis.

Minimum inhibitory concentration (MIC) data for the target pathogens (wild type distribution) are presented in the table below.

The following tildipirosin breakpoints have been established for swine respiratory disease (according to CLSI Guideline VET02 A3):

S: susceptible; I: intermediate; R: resistant

Resistance to macrolides generally results from three mechanisms: (1) the alteration of the ribosomal target site (methylation), often referred to as MLSB resistance as it affects macrolides, lincosamides and group B streptogramins, (2) the utilisation of active efflux mechanism; (3) the production of inactivating enzymes. Generally, cross-resistance between tildipirosin and other macrolides, lincosamides or streprogramins is to be expected.

Data were collected on zoonotic bacteria and commensals. MIC values for Salmonella were reported to be in the range of 4–16 ^g/ml, and all strains were wild type. For E. coli , Campylobacter and Enterococci , both wild type and non-wild type phenotypes were observed (MIC range 1– > 64 ^g/ml).

• 5.2 Pharmacoki­netic particulars

Tildipirosin administered intramuscularly to pigs at a single dose of 4 mg/kg body weight was rapidly absorbed reaching average peak plasma concentration of 0.9 ^g/ml within 23 minutes (Tmax).

Macrolides are characterised by their extensive partitioning into tissues.

Accumulation at the site of respiratory tract infection is demonstrated by high and sustained tildipirosin concentrations in lung and bronchial fluid (collected post mortem), which far exceed those in blood plasma. The mean terminal half-life is 4.4 days.

In vitro binding of tildipirosin to porcine plasma proteins is limited with approximately 30 %.

In pigs, it is postulated that the metabolism of tildipirosin proceeds by reduction and sulphate conjugation with subsequent hydration (or ring opening), by demethylation, by dihydroxylation and by S-cysteine and S-glutathione conjugation.

The mean total excretion of the total dose administered within 14 days was about 17% in urine and 57% in faeces.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Citric acid monohydrate

Propylene glycol

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: 2 years.

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

6.4 Special precautions for storage

Do not store above 25 °C.

• 6.5 Nature and composition of immediate packaging

Type I amber glass vial with a chlorobutyl rubber stopper and an aluminium cap.

Box containing 1 vial of 20 ml, 50 ml, 100 ml or 250 ml.

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

Intervet International B. V.

Wim de Korverstraat 35

5831 AN Boxmeer

The NETHERLANDS

8. MARKETING AUTHORISATION NUMBER(S)

EU/2/11/124/001–004

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 6 May 2011. Date of last renewal:

10. DATE OF REVISION OF THE TEXT

Detailed information on this veterinary medicinal product is available on the website of the European

Medicines Agency.

PROHIBITION OF SALE, SUPPLY AND/OR USE

Not applicable.

• 1. NAME OF THE VETERINARY MEDICINAL PRODUCT

ZUPREVO 180 mg/ml solution for injection for cattle

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

One ml contains:

Active substance:

Tildipirosin            180 mg.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for injection.

Clear yellowish solution.

4. CLINICAL PARTICULARS4.1 Target species

Cattle

• 4.2 Indications for use, specifying the target species

For the treatment and prevention of bovine respiratory disease (BRD) associated with Mannheimia haemolytica , Pasteurella multocida and Histophilus somni sensitive to tildipirosin.

The presence of the disease in the herd should be confirmed before preventive treatment.

4.3 Contraindications

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

Do not administer simultaneously with other macrolides or lincosamides (see section 4.8)

• 4.4 Special warnings

None.

• 4.5 Special precautions for use

Special precautions for use in animals

Whenever possible, the veterinary medicinal product should only be used based on susceptibility testing.

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

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

Tildipirosin may cause sensitisation by skin contact. If accidental skin exposure occurs, wash the skin immediately with soap and water. If accidental eye exposure occurs, flush eyes immediately with clean water.

Wash hands after use.

Special caution should be taken to avoid accidental self-injection, as toxicology studies in laboratory animals showed cardiovascular effects after intramuscular administration of tildipirosin. In case of accidental self-injection, seek medical advice immediately and show the package leaflet or the label to the physician.

Do not use in automatically powered syringes which have no additional protection system.

• 4.6 Adverse reactions (frequency and seriousness)

In very rare cases, anaphylactic reactions, with a potentially fatal outcome, might occur.

Pain on injection and injection site swellings are very common in treated animals. Following the maximum recommended injection site volume of 10 ml, injection site swellings may be associated with pain on palpation for about one day in individual animals. The swellings are transient and will usually resolve within 7 to 16 days; in individual animals swellings may persist for 21 days.

Pathomorphological injection site reactions will largely resolve within 35 days.

The frequency of adverse reactions is defined using the following convention:

• – very common (more than 1 in 10 animals displaying adverse reactions during the course of one treatment)

• – common (more than 1 but less than 10 animals in 100 animals)

• – uncommon (more than 1 but less than 10 animals in 1,000 animals)

• – rare (more than 1 but less than 10 animals in 10,000 animals)

• – very rare (less than 1 animal in 10,000 animals, including isolated reports).

• 4.7 Use during pregnancy and lactation

The safety of the veterinary medicinal product has not been established during pregnancy and lactation. However, there was no evidence for any selective developmental or reproductive effects in any of the laboratory studies. Use only accordingly to the benefit-risk assessment by the responsible veterinarian.

4.8 Interaction with other medicinal products and other forms of interaction

There is cross resistance with other macrolides. Therefore, the product should not be administered with antimicrobials with a similar mode of action such as other macrolides or lincosamides.

• 4.9 Amounts to be administered and administration route

Subcutaneous use.

Administer 4 mg tildipirosin/kg body weight (equivalent to 1 ml/45 kg body weight) once only. For treatment of cattle over 450 kg body weight, divide the dose so that no more than 10 ml are injected at one site.

The rubber stopper of the vial may be safely punctured up to 20 times. Otherwise, the use of a multiple-dose syringe is recommended.

To ensure correct dosage, bodyweight should be determined as accurately as possible to avoid underdosing.

It is recommended to treat animals in the early stages of the disease and to evaluate the response to treatment within 2 to 3 days after injection. If clinical signs of respiratory disease persist or increase, treatment should be changed using another antibiotic, and continued until clinical signs have resolved.

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

In calves, a single subcutaneous injection of 10 times the recommended dose (40 mg/kg body weight) and repeated subcutaneous administration of tildipirosin (on three occasions in intervals of 7 days) at 4, 12 and 20 mg/kg (1, 3 and 5 times the recommended clinical dose) were well tolerated, apart from transient clinical signs attributed to injection site discomfort and injection site swellings associated with pain in some animals.

• 4.11 Withdrawal period

Cattle (meat and offal): 47 days.

Not authorised for use in lactating 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.

5. PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: antibacterials for systemic use, macrolides.

ATCvet code: QJ01FA96.

5.1 Pharmacodynamic properties

Tildipirosin is a 16-membered semi-synthetic macrolide antimicrobial agent. Three amine substituents at the macrocyclic lactone ring result in a tri-basic character of the molecule. The product has a long duration of action; however, the exact clinical effect duration after a single injection is unknown.

Macrolides in general are bacteriostatic antibiotics but for certain pathogens can be bactericidal. They inhibit essential protein biosynthesis by virtue of their selective binding to bacterial ribosomal RNA and act by blocking the prolongation of the peptide chain. The effect is generally time-dependent.

The antimicrobial activity spectrum of tildipirosin includes:

Mannheimia haemolytica , Pasteurella multocida and Histophilus somni , the bacterial pathogens most commonly associated with bovine respiratory disease (BRD). In vitro , the effect of tildipirosin is bactericidal against M. haemolytica and H. somni , and bacteriostatic against P. multocida.

Minimum inhibitory concentration (MIC) data for the target pathogens (wild type distribution) are presented in the table below.

The following tildipirosin breakpoints have been established for bovine respiratory disease (according to CLSI Guideline VET02 A3):

S: susceptible; I: intermediate; R: resistant

Resistance to macrolides generally results from three mechanisms: (1) the alteration of the ribosomal target site (methylation), often referred to as MLSB resistance as it affects macrolides, lincosamides and group B streptogramins; (2) the utilisation of active efflux mechanism; (3) the production of inactivating enzymes. Generally, cross-resistance between tildipirosin and other macrolides, lincosamides or streptogramins is to be expected.

Data were collected on zoonotic bacteria and commensals. MIC values for Salmonella were reported to be in the range of 4–16 ^g/ml, and all strains were wild type. For E. coli , Campylobacter and Enterococci , both wild type and non-wild type phenotypes were observed (MIC range 1→ 64 ^g/ml).

• 5.2 Pharmacoki­netic particulars

Tildipirosin administered subcutaneously to cattle at a single dose of 4 mg/kg body weight resulted in rapid absorption with average peak plasma concentration of 0.7 ^g/ml within 23 minutes (Tmax) and high absolute bioavailability (78.9%).

Macrolides are characterised by their extensive partitioning into tissues.

Accumulation at the site of respiratory tract infection is demonstrated by high and sustained tildipirosin concentrations in lung and bronchial fluid, which far exceed those in blood plasma. The mean terminal half-life is approximately 9 days.

In vitro binding of tildipirosin to bovine plasma and bronchial fluid proteins is limited with approximately 30%.

In cattle, it is postulated that metabolism of tildipirosin proceeds by cleavage of the mycaminose sugar moiety, by reduction and sulphate conjugation with subsequent hydration (or ring opening), by demethylation, by mono- or dihydroxylation with subsequent dehydration and by S-cysteine and S-glutathione conjugation.

The mean total excretion of the total dose administered within 14 days was about 24% in urine and 40% in faeces.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Citric acid monohydrate

Propylene glycol

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: 2 years.

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

6.4 Special precautions for storage

Do not store above 25 °C.

• 6.5 Nature and composition of immediate packaging

Type I amber glass vial with chlorobutyl rubber stopper and an aluminium cap.

Box containing 1 vial of 20 ml, 50 ml, 100 ml or 250 ml.

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

7. MARKETING AUTHORISATION HOLDER

Intervet International B. V.

Wim de Korverstraat 35

5831 AN Boxmeer

The NETHERLANDS

8. MARKETING AUTHORISATION NUMBERS

EU/2/11/124/005–008

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 6 May 2011.

Date of last renewal: