METAFLOX 250 (oral powder)

Powder from light yellow to yellow-brown in colour with an odour characteristic of its components.

1 g of the product contains the active substances:

- doxycycline hyclate — 250 mg;

- colistin sulfate — 2,400,000 IU.

Excipient: tartaric acid or citric acid.

ATC vet classification code QJ01 — antibacterial veterinary medicinal products for systemic use. QJ01RA95 — Polymyxins, combinations with other antimicrobial agents.

Doxycycline is a bacteriostatic antibiotic belonging to the tetracycline group. It exerts a bacteriostatic effect by inhibiting microbial protein synthesis through blocking the binding of aminoacyl-transfer RNA (tRNA) to the messenger RNA (mRNA)–ribosome complex. Doxycycline has a broad spectrum of antimicrobial activity against gram-positive (Staphylococcus spp., Diplococcus pneumoniae, Streptococcus spp., Bacillus anthracis, Clostridium tetani, Clostridium perfringens, Listeria monocytogenes) and gram-negative (Haemophilus influenzae, E. coli, Enterobacter spp., Klebsiella spp., Salmonella spp., Shigella spp., Yersinia spp., Pasteurella spp., Bordetella bronchiseptica) bacteria, as well as mycoplasmas (Mycoplasma spp.), rickettsiae (Rickettsia spp.) and chlamydiae (Chlamydia spp.).

Colistin is an antibiotic of the polymyxin group, synthesised by the aerobic spore-forming rod Bacillus polymyxa. It exerts a bactericidal action against gram-negative bacteria (E. coli, Salmonella spp., Pseudomonas spp.) by binding to the phospholipids of the cytoplasmic membrane, increasing its permeability to both intracellular and extracellular components, which leads to disruption of cellular barriers and lysis of the bacterial cell.

Following oral administration, doxycycline is almost completely absorbed in the intestine (93–100%) and reaches peak serum concentration within 2–4 hours. Therapeutic concentration is maintained for 18–24 hours. It is distributed throughout the body, reaching high concentration levels in the lungs, kidneys, liver, adipose tissue, as well as in bones and dentine. The presence of feed in the intestine does not affect doxycycline absorption. The concentration of doxycycline in the lungs of calves and pigs is approximately twice as high as in blood plasma. Doxycycline is detected in cerebrospinal fluid at low concentrations, but these do not reach a therapeutic level. The half-life of doxycycline is: 4–9 hours in cattle; 10 hours in horses; 7 hours in pigs; 3 hours in sheep. Unlike other tetracyclines, doxycycline is excreted unchanged, primarily via bile (more than 60%).

Following oral administration, colistin is absorbed to a limited extent from the gastrointestinal tract of calves and pigs. Colistin does not accumulate in organs and tissues and is not affected by digestive enzymes; as a result, a high concentration of the antibiotic is established in the gastrointestinal tract. No colistin was detected in the serum of these animal species. In the serum of chicks, colistin was detected at a low concentration 6 hours after administration via drinking water.

In contrast to the low concentrations of colistin in serum and tissues, high and sustained concentrations are consistently present throughout the various sections of the gastrointestinal tract. Higher colistin concentrations are observed in the large intestine and caecum.

Colistin is eliminated from the animal body via faeces.

Calves up to 8 weeks of age: treatment of septicaemia, as well as respiratory tract diseases (bronchopneumonia, rhinotracheitis and others) and gastrointestinal diseases (colibacillosis, salmonellosis) caused by microorganisms susceptible to doxycycline and colistin.

Pigs: treatment of septicaemia, as well as respiratory tract diseases (bronchopneumonia, pleuropneumonia, atrophic rhinitis and others) and gastrointestinal diseases (colibacillosis, salmonellosis) caused by microorganisms susceptible to doxycycline and colistin.

Domestic poultry (broiler chickens, parent flock, replacement pullets, turkeys): treatment of colibacillosis, salmonellosis, ornithosis, septicaemia, as well as respiratory tract diseases caused by microorganisms susceptible to doxycycline and colistin.

- calves up to 8 weeks of age — 2,0 g of the product per 100 kg body weight twice daily, administered via drinking water, feed, milk or milk replacer (equivalent to 10 mg doxycycline and 96,000 IU colistin sulfate per 1 kg body weight per day) for 5 days;

- pigs — via drinking water at a dose of 4,0 g of the product per 100 kg body weight (equivalent to 10 mg doxycycline and 96,000 IU colistin sulfate per 1 kg body weight per day) once daily, or 400 g of the product per 1,000 L of drinking water daily, for 5 days;

- domestic poultry (broiler chickens, parent flock, replacement pullets, turkeys) — via drinking water at a dose of 0,5–1,0 g of the product per 10 kg body weight per day (equivalent to 12,5–25,0 mg doxycycline and 120,000–240,000 IU colistin sulfate per 1 kg body weight per day), or 100–200 g of the product per 1,000 L of drinking water daily, for 4–7 days.

Depending on the recommended dose and body weight of the poultry, the required daily amount of the product shall be calculated using the following formula:

where: M — mg of the product per litre of drinking water;

X — dose of the product (mg per 1 kg body weight of the animal);

m — average body weight (kg) of the birds under treatment;

V — average daily water consumption (L) per animal.

To prepare the solution, pour the required amount of drinking water (preferably warm) into a small container and add the product in small portions with continuous stirring until the powder is completely dissolved. The concentrate prepared in this manner (ratio: 0.2–0.4 kg of the product in 10 L of drinking water) is immediately added to the required volume of drinking water, in accordance with the water consumption norms for the respective age categories of poultry. A fresh solution shall be prepared daily.

Hypersensitivity to tetracycline-group products and colistin.

Do not use in animals with severe hepatic or renal impairment.

Do not use in laying hens whose eggs are intended for human consumption, or in ruminants with functionally developed forestomachs.

Do not use concomitantly with antibiotics having bactericidal activity, such as penicillins, cephalosporins, quinolones and cycloserine. Do not use concomitantly with antacids, kaolin or products containing the cations Mg²⁺, Al³⁺, Ca²⁺, as the latter bind to doxycycline and impair its absorption.

Do not use when resistant strains of the causative agent have been identified.

Not observed at recommended doses.

In isolated cases, allergic reactions (skin rash, pruritus and oedema) and digestive disturbances (anorexia, vomiting, diarrhoea) may occur. Should these arise, administration of the product shall be discontinued and desensitising therapy initiated.

High doses or prolonged use of the product may cause a neurotoxic effect (e.g., ataxia).

Due to the risk of development of microbial resistance to doxycycline and/or colistin, use of the product is not recommended for mild-to-moderate infections. Use of the product shall be based on susceptibility testing of microorganisms to doxycycline and colistin. Microbiological confirmation of diagnosis and susceptibility testing of the causative agents shall be performed prior to prescribing the product. Use of the product is prohibited where resistance of microorganisms to the active substances has been established. When using the product, the norms set out in the Procedure for the Use of Antimicrobial Veterinary Medicinal Products in Veterinary Medicine of Ukraine shall be observed.

Do not use in laying hens whose eggs are intended for human consumption.

The product is not recommended for use in animals during pregnancy or lactation due to the potential neurotoxic effect. Use of the product is permitted only when it is evident that the benefit of use outweighs the potential adverse consequences.

No data are available regarding embryotoxic, teratogenic or mutagenic effects of doxycycline and colistin.

Do not use concomitantly with antibiotics of the penicillin, polymyxin and cephalosporin groups, quinolones or cycloserine.

Do not use concomitantly with products containing the cations Mg²⁺, Al³⁺, Ca²⁺, as the latter bind to doxycycline and impair its absorption.

It is recommended that the interval between administration of any other product containing polyvalent cations and this product should be 1–2 hours, as such cations limit the absorption of tetracyclines (doxycycline).

Doxycycline potentiates the effect of anticoagulants.

The product is not recommended for mixing with other medicinal products.

Slaughter of animals for meat is permitted 8 days (pigs), 7 days (poultry) and 14 days (calves) after the last administration of the product. Meat obtained prior to the specified withdrawal period shall be disposed of or fed to non-productive animals, at the discretion of the attending veterinarian.

Polyethylene film bags in accordance with GOST 10354 or other polymeric film bags of 1, 2, 5, 10, 50, 100 and 500 g, 1, 20 and 25 kg.

Polymeric containers of 100 and 500 g, 1 kg.

Store in a dry, dark place, out of reach of children, at a temperature of 5 °C to 25 °C.

2 years.

Shelf life after first opening of the package — 14 days, provided the opened container is stored at a temperature of 15 °C to 25 °C in a dry, light-protected place.

Shelf life of the product after dilution in drinking water — 24 hours.