MSD ZUPREVO 250 ml VET ONLY (S4)

PHARMACOLOGICAL ACTION

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 somnithe bacterial pathogens most commonly associated with Bovine Respiratory Disease (BRD).
In vitro, the effect of tildipirosin is bactericidal against M. haemolytica, P. multocida and H. somni, and bacteriostatic against P. multocida.
MICdata for the target pathogens (wild type distribution) are presented in the table below

(2003 – 2009).

Species Range (µg/mℓ) MIC50 (µg/mℓ) MIC90 (µg/mℓ)
Mannheimia haemolytica (n = 88) 0,125 – 2,0 0,5 1,0
Pasteurella multocida (n = 105) 0,125 – 2,0 0,5 1,0
Histophilus somni (n = 63) 0,5 – 8,0 2,0 4,0
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 may be expected.

Pharmacokinetic properties

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 µg/mℓ within 23 minutes (Tmax) and high absolute bioavailability of 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 the 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 to 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.

INDICATIONS

For the treatment and metaphylactic management of Bovine Respiratory Disease (BRD) associated with Mannheimia haemolytica, Pasturella multocida, and Histophilis somni sensitive to tildipirosin.

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

CONTRAINDICATIONS

NOT INDICATED FOR USE IN SWINE.

Do not use in cases of hypersensitivity to macrolide antibiotics, citric acid monohydrate or propylene glycol.

Do not use in lactating cattle 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.

WARNINGS

Withdrawal period: Meat and offal: 47 days.

SAFETY IN PREGNANCY AND LACTATION

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

DOSAGE AND DIRECTIONS FOR USE

Subcutaneous injection.

Administer 4,0 mg tildipirosin/kg body weight (equivalent to 1 mℓ/45 kg body weight) once only.

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 class of antibiotics, and continued until clinical signs have resolved.

Advice on correct administration.

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 multi-dose syringe is recommended.

To ensure correct dosage, body weight should be determined as accurately as possible to avoid under dosing.

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

SIDE EFFECTS AND SPECIAL PRECAUTIONS

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 1 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. Injection site reactions will usually resolve within 35 days.

After administration of Zuprevo® 18%, slight bleeding at the injection site might be noted in some animals.

Head shaking, bucking, tail twitching, stamping, kicking, twisting of the neck, pawing, flexing and extending the neck, circling, kneeling, agitation, and lifting of the forefeet has been observed in some animals.

If any serious side effects or other effects not mentioned in this package insert are noticed, please inform your veterinarian.

SPECIAL PRECAUTIONS FOR USE

Precautions for the person administering the product

Special precautions should be taken to avoid accidental self-injection, as toxicological studies in laboratory animals showed cardiovascular effects after intramuscular administration of tildipirosin.

In case of accidental self-injection, seek medical advice and show this package insert or label to the health care professional.

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.

Precautions for use in animals

Wherever possible, Zuprevo® 18% 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.

SPECIAL PRECAUTIONS FOR THE DISPOSAL OF UNUSED PRODUCT OR WASTE MATERIALS, IF ANY

Ask your veterinarian or pharmacist how to dispose of medicines which are no longer required. These measures should help to protect the environment.

INTERACTION

In the absence of compatibility studies, Zuprevo® 18% must not be mixed with other veterinary medicines.

There is cross resistance with other macrolides. Do not administer Zuprevo® 18% with antimicrobials with a similar mode of action such as other macrolides or lincosamides.

KNOWN SIGNS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT

Overdoses of 10 times the recommended dose as well as repeated subcutaneous administration of the veterinary medicinal product only led to transient clinical signs attributed to injection site discomfort and injection site swellings associated with pain in some animals.Treatment is symptomatic and supportive.

IDENTIFICATION

Clear, yellowish solution.

PRESENTATION

Type 1 amber glass vial, with a grey chlorobutyl rubber stopper and an aluminium cap with a light grey polypropylene tear-off lid.

Carton containing 1 x 20 mℓ, 50 mℓ, 100 mℓ or 250 mℓ vial.

Multi-vial box containing 4 x 250 mℓ vials, each packed in individual cartons.

Not all pack sizes may be marketed.

STORAGE INSTRUCTIONS

Store at or below 25 °C.

Use the contents of the vial within 28 days following withdrawal of the first dose. Discard any unused solution.

Do not use after the expiry date which is stated on the vial.

KEEP OUT OF REACH AND SIGHT OF CHILDREN AND UNINFORMED PERSONS AND ANIMALS.

REGISTRATION NUMBER

13/17.1.4/01 (Act 101/1965)

Namibia Reg. Nr. V18/17.1.4/1415 [NS2]

REGISTRATION HOLDER

Intervet South Africa (Pty) Ltd.

20 Spartan Road, Spartan

1619, RSA

Tel: +27 (0) 11 923 9300

E-mail: msdahza@msd.com

www.msd-animal-health.co.za

DATE OF NOTIFICATION OF APPROVAL OF THIS SCIENTIFIC PACKAGE INSERT

29 July 2016