SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE VETERINARY MEDICINAL PRODUCT

DFV DOXIVET 200 mg/ml, solution for use in drinking water for pigs and chickens.

ES: DFV DOXYCYCLINE 200 mg/ml, solution for use in drinking water for pigs and chickens

IT: Doxycycline DFV 200 mg/ml, solution for use in drinking water for pigs and chickens

SE: Doxycycline Divasa-Farmavic 200 mg/ml lösning för användning I dricksvatten

DK: Doxycycline Divasa-Farmavic Vet.

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Composition for 1 ml:

Active substance:

Doxycycline hyclate 230 mg

Equivalent to 200 mg doxycycline base

Excipients:

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Solution for use in drinking water

Clear yellow-brown solution.

4. CLINICAL PARTICULARS

4.1 Target species

Pigs and chickens (broiler, pullet, breeder).

4.2 Indications for use, specifying the target species

Pigs: For the treatment of the clinical signs associated with porcine respiratory disease caused by Actinobacillus pleuropneumoniae, Pasteurella multocida, and Mycoplasma hyopneumoniae susceptible to doxycycline.

Chickens: Where clinical disease is present in the flock, to reduce mortality, morbidity, and clinical signs and to reduce lesions due to Pasteurellosis caused by Pasteurella multocida or to reduce morbidity and lesions in respiratory infections caused by Ornithobacterium rhinotracheale (ORT).

4.3 Contraindications

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

Do not use in animals with an impaired liver function.

4.4 Special warnings for each target species

None.

4.5 Special precautions for use

Special precautions for use in animals

Due to likely variability (time, geographical) in susceptibility of bacteria for doxycycline, especially susceptibility of A. pleuropneumoniae and O. rhinotracheale may differ from country to country and even farm to farm, bacteriological sampling and susceptibility testing are recommended.

Use of the product should be based on culture and sensitivity of micro-organisms from diseased cases on farm. If this is not possible, therapy should be based on local (regional, farm level) epidemiological information about susceptibility of the target bacteria.

As eradication of the target pathogens may not be achieved, medication should therefore be combined with good management practices, e.g. good hygiene, proper ventilation, no overstocking.

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

If you know you are allergic to the tetracycline class of antibiotics, special care should be taken when handling this product or the medicated solution.

During preparation and administration of the medicated drinking water, skin contact with the product should be avoided. Wear impermeable gloves (e.g. rubber or latex) when applying the product.

In the event of eye or skin contact, rinse the affected area with large amounts of clean water and if irritation occurs, seek medical attention. Wash hands and contaminated skin immediately after handling the product.

If you develop symptoms following exposure such as skin rash, you should seek medical advice and show this warning to the physician. Swelling of the face, lips or eyes, or difficulty with breathing are more serious symptoms and require urgent medical attention.

Do not smoke, eat or drink while handling the product.

Avoid direct contact with skin and eyes when handling the product to prevent sensitisation and contact dermatitis.

4.6 Adverse reactions (frequency and seriousness)

Tetracyclines may - in very rare cases (less than 1 animal in 10,000, including isolated reports) - induce photosensitivity and allergic reactions. If suspected adverse reactions occur, treatment should be discontinued. Inform your veterinary surgeon if adverse reactions occur that are not stated.

4.7 Use during pregnancy, lactation or lay

Doxycycline has a low affinity for forming complexes with calcium and studies have demonstrated that doxycycline scarcely affects skeleton formation. No negative effects were observed in poultry after the administration of therapeutic doses of doxycycline.

In the absence of specific studies the use of the product is not recommended during pregnancy or lactation.

4.8 Interaction with other medicinal products and other forms of interaction

Do not combine with antibiotics that are bacteriocidal e.g. penicillins or cephalosporins.

Absorption of doxycycline can be decreased in the presence of high quantities of calcium, iron, magnesium or aluminium in the diet. Do not administer together with antacids, kaolin and iron preparations.

It is advised that the interval between the administration of other products containing polyvalent cations should be 1-2 hours because they limit the absorption of tetracyclines.

Doxycycline increases the action of anticoagulants.

The solubility of the product is pH dependent and will precipitate if mixed in alkaline solution.

Do not store the drinking water in metallic containers.

4.9 Amounts to be administered and administration route

Administration orally with the drinking water.

The recommended dose in pigs is:

12.5 mg doxycycline hyclate (0.054 ml product) per kg body weight per day for 4 consecutive days. If no improvement in clinical signs is seen within this time, the diagnosis should be reviewed and treatment changed. In case of severe infections the medication period may be prolonged for a maximum of 8 consecutive days as determined by the attending veterinary surgeon.

The recommended dose in chickens is:10 mg doxycycline hyclate (0.043ml product) per kg body weight per day for 3-4 consecutive days in case of infections caused by P. multocida and 20 mg doxycycline hyclate (0.087ml product) per kg body weight per day for 3-4 consecutive days in case of infections caused by O. rhinotracheale.

Based on the dose to be used, and the number and weight of the animals to be treated, the exact daily amount of product can be calculated. The following formula can be used to calculate the concentration of the product in drinking water:

..... ml product/ kg body weight / day	x	mean body weight (kg) of animals to be treated	=	.... ml product per l drinking water
mean daily water consumption (l) per animal at the previous day

To ensure a correct dosage body weight should be determined as accurately as possible. The uptake of medicated drinking water depends on the clinical condition of the animals. In order to obtain the correct dosage the concentration of doxycycline has to be adjusted accordingly. The use of suitably calibrated equipment is recommended if part containers are used. The daily amount is to be added to the drinking water such that all medication will be consumed in 24 hours. Medicated drinking water should be refreshed or replaced every 24 hours. Solubility of the product is pH dependent and it may precipitate if it is mixed in hard alkaline drinking water. During the treatment period animals should not have access to other water sources than the medicated water.

Weight can also be used to measure the product quantity to be added in drinking water. In this case the density correction should be used, according to the following formula:

Amount to be added in drinking water (g/L)

=

amount to be added in drinking water (ml/L) x 1.075 (g/ml)

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

Overdoses up to 1.6 times the label recommended dose resulted in no clinical signs that could be attributed to treatment. Poultry tolerate double overdoses of doxycycline (40 mg/kg body weight) without any clinical effect.

4.11 Withdrawal period(s)

Pigs:

- Meat and offal: 4 days

Chickens:

- Meat and offal: 3 days, following a dose rate of 10 mg/kg body weight for 4 days.

- Meat and offal: 12 days, following a dose rate of 20 mg/kg body weight for 4 days.

- Eggs: Not authorised for use in laying birds producing eggs for human consumption.

Do not use within 4 weeks of onset of the laying period

5. PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Antiinfectives for systemic use, antibacterials for systemic use, tetracycline, doxycycline

ATCvet code: QJ01AA02

5.1 Pharmacodynamic properties

Doxycycline belongs to the group of the tetracycline antibiotics. These antibiotics have a broad spectrum of antimicrobial activity, sharing the same basic structure of polycyclic naphthacenecarboxamide.

Doxycycline is primarily a bacteriostatic drug. It exerts its action by inhibiting the protein synthesis of the bacterial cell. Inhibition of bacterial protein synthesis results in disturbance of all functions necessary for the life of bacteria. Especially cell-division and the formation of the cell wall are impaired.

Doxycycline is a broad-spectrum antibiotic, active against a large number of Gram-positive and Gram-negative, aerobe and anaerobe micro-organisms, MycoplasmataFor Ornithobacterium rhinotrachealeresults demonstrate a great variation from high to low susceptibility, depending on the geographical region where isolates came from.

In pig pathogens resistance against doxycycline may also vary; especially susceptibility figures of A. pleuropneumoniae may differ from country to country and even farm to farm.

Four resistance mechanisms acquired by microorganisms against tetracyclines in general have been reported: Decreased accumulation of tetracyclines (decreased permeability of the bacterial cell wall and active efflux), protein protection of the bacterial ribosome, enzymatic inactivation of the antibiotic and rRNA mutations (preventing the tetracycline binding to ribosome). Tetracycline resistance is usually acquired by means of plasmids or other mobile elements (e.g. conjugative transposones). Cross resistance between tetracyclines has also been described. Due to the greater liposolubility and greater facility to pass through cell membranes (in comparison to tetracycline), doxycycline retains a certain degree of efficacy against microorganisms with acquired resistance to tetracyclines.

Doxycycline is absorbed in the stomach and the first part of the duodenum. Compared to the older tetracyclines the absorption of doxycycline is less affected by the presence of bivalent cations in food. Bioavailability in non-fasted pigs is approximately 21%.

Following oral administration at a dose of 12.8 mg/kg body weight, steady state concentrations during medication range between a C_min of 0.40 μg/ml in the early morning to a C_max of 0.87 μg/ml in the late afternoon in pigs.

Following administration of doxycycline hyclate at an actual dose of 21 mg/kg body weight to chickens mean plasma concentrations above 1 μg/ml were reached within 6 hours and lasted for 6 hours after cessation of medication. From 24 h up to 96 h after start of treatment the doxycycline plasma concentrations exceeded 2 μg/ml. Following administration of doxycycline hyclate at an actual dose of 10 mg/kg body weight steady state plasma concentrations ranged from 0.75 to 0.93 μg/g between 12 and 96 hours after start of medication.

Because doxycycline is highly lipid soluble, it has a good tissue penetration. Respiratory tract tissue: plasma ratios of 1.3 (healthy lungs), 1.9 (pneumonic lungs) and 2.3 (nasal mucosa) have been reported for doxycycline. Plasma protein binding is high (over 90%).

Doxycycline is scarcely metabolised. Doxycycline is primarily excreted with the faeces.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Ethanol anhydrous

Propylene glycol

6.2 Incompatibilities

Solubility of doxycycline is pH dependent. Precipitation will occur in an alkaline solution. In the absence of compatibility studies, this 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: 6 months.

Shelf-life after dilution or reconstitution according to directions: 24 hours after dilution in drinking water.

6.4. Special precautions for storage

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

6.5 Nature and composition of immediate packaging

Nature of container:

HDPE container with tamper-evident aluminium seal and HDPE screw cap.

Package sizes:

1 litre and 5 litres.

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 product should be disposed of in accordance with local requirements.

7. MARKETING AUTHORISATION HOLDER

DIVASA-FARMAVIC S.A.

Ctra. Sant Hipòlit, km 71

08503 Gurb-Vic

Barcelona (Spain)

8. MARKETING AUTHORISATION NUMBER

Vm 33229/4001

9. DATE OF FIRST AUTHORISATION

12 July 2011

10. DATE OF REVISION OF THE TEXT

May 2016

PROHIBITION OF SALE, SUPPLY AND/OR USE

Not applicable.

26 May 2016