SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE VETERINARY MEDICINAL PRODUCT

Gabbrovet Multi 140 mg/ml Solution for Use in Drinking Water/Milk for Pre-ruminant Cattle and Pigs

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml contains:

Active substance:

Paromomycin (as sulfate) 140 mg

(equivalent to 140 000 IU of paromomycin activity)

(equivalent to approximately 200 mg of paromomycin sulfate) Excipients:

Benzyl alcohol	(E1519)	7.5 mg
Sodium metabisulfite	(E223)	3.0 mg

For the full list of excipients, see section 6.1

3. PHARMACEUTICAL FORM

Solution for use in drinking water, milk or milk replacer Pale yellow to yellow solution

4. CLINICAL PARTICULARS

4.1 Target species

Cattle (pre-ruminant cattle and new-born calves), pigs 4.2 Indications for use, specifying the target species

Pre-ruminant cattle:

Colibacillosis

Treatment of gastro-intestinal infections caused by Escherichia coli susceptible to paromomycin.

Cryptosporidiosis

Treatment of infections caused by diagnosed Cryptosporidium parvum, by reduction of diarrhoea and reduction of faecal oocyst shedding. Administration has to start within 24 hours after the onset of diarrhoea.

Pigs:

Colibacillosis

Treatment of gastro-intestinal infections caused by Escherichia coli susceptible to paromomycin.

4.3 Contraindications

Do not use in animals with known hypersensitivity to paromomycin, other aminoglycosides or any of the excipients.

Do not use in cases with impaired function of the kidneys or liver.

Do not use in ruminating animals.

Do not use in turkeys due to the risk of selection for antimicrobial resistance in intestinal bacteria.

4.4 Special warnings for each target species

Cross-resistance has been shown between paromomycin and neomycin in Enterobacterales. Use of the product should be carefully considered when susceptibility testing has shown resistance to aminoglycosides because its effectiveness may be reduced.”

Treatment with the veterinary medicinal product reduced the impact of cryptosporidiosis on the daily bodyweight gain.

4.5 Special precautions for use

Special precautions for use in animals

The use of the veterinary medicinal product should be combined with good management practices e.g. good hygiene, proper ventilation, no overstocking.

Since the product is potentially ototoxic and nephrotoxic, it is recommended to assess kidney function. Special care should be taken when considering administration of the veterinary medicinal product to newborn animals due to the known higher gastrointestinal absorption of paromomycin in neonates. This higher absorption could lead to an increased risk of oto-and nephrotoxicity. The use of the veterinary medicinal product in calves of 5 days or less should be based on benefitrisk assessment by the responsible veterinarian.

As with any antiparasiticide, frequent and repeated use of antiprotozoals from the same class may lead to the development of resistance.

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

Use of the 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.

Colibacillosis

The uptake of medication by animals can be altered as a consequence of illness. In case of insufficient uptake of water/milk animals should be treated parenterally using a suitable injectable veterinary medicinal product following the advice of the veterinarian.

Prolonged or repeated use of the veterinary medicinal product should be avoided by improving management practices and through cleansing and disinfection.

Use of the veterinary medicinal product deviating from the given instructions may increase the prevalence of bacteria resistant to paromomycin and may decrease the effectiveness of treatment with aminoglycosides due to the potential for crossresistance.

Aminoglycosides are considered as critical in human medicine. Consequently, they should not be used as a first intention antimicrobial treatment in veterinary medicine.

Cryptosporidiosis

Calves should only receive the treatment upon confirmation of cryptosporidial oocysts in their faeces.

The product should only be used in individual animals.

Do not use on an empty stomach. For treatment of anorexic calves, the product should be administered in half a litre of an electrolyte solution. The animals should receive enough colostrum according to good breeding practice.

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

- This product contains paromomycin and benzyl alcohol, which can cause allergic reactions in some people.

- People with known hypersensitivity (allergy) to paromomycin or any other aminoglycosides and/or benzyl alcohol should avoid contact with the veterinary medicinal product.

- This product is slightly irritant to the eye. Avoid contact with the skin and eyes.

- Personal protective equipment consisting of protective clothing and impervious gloves should be worn when handling the veterinary medicinal product.

- In the event of accidental contact with the skin or eyes, rinse with plenty of water.

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

- Do not eat, drink and smoke when handling the veterinary medicinal product.

- Do not ingest. In case of accidental ingestion, seek medical advice immediately and show the label to the physician. - Wash hands after use.

4.6 Adverse reactions (frequency and seriousness)

In rare occasions soft faeces have been observed.

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

- very common (more than 1 in 10 animals treated displaying adverse reaction(s))

- common (more than 1 but less than 10 animals in 100 animals treated)

- uncommon (more than 1 but less than 10 animals in 1,000 animals treated)

- rare (more than 1 but less than 10 animals in 10,000 animals treated)

- very rare (less than 1 animal in 10,000 animals treated, including isolated reports) Aminoglycoside antibiotics such as paromomycin can cause oto- and nephrotoxicity.

4.7 Use during pregnancy, lactation or lay

Laboratory studies in the rat and rabbit have not produced any evidence of teratogenic, foetotoxic or maternotoxic effects. The use is not recommended during pregnancy.

4.8 Interaction with other medicinal products and other forms of interaction

General anaesthetics and muscle relaxing products increase the neuro-blocking effect of aminoglycosides. This may cause paralysis and apnoea.

Do not use concurrently with strong diuretics and potentially oto- or nephrotoxic substances.

4.9 Amounts to be administered and administration route

Oral use.

To ensure a correct dosage bodyweight should be determined as accurately as possible.

Cattle (pre-ruminant cattle):

Colibacillosis

Duration of treatment: 3-5 days.

Administration in milk/milk replacer.

Recommended dosage: 1.25 – 2.5 ml of veterinary medicinal product/10 kg BW/day, equivalent to 17500 - 35000 IU of paromomycin per kg BW/day (i.e. approximately 25-50 mg paromomycin sulfate per kg BW/day).

Cattle (newborn calves):

Cryptosporidiosis

Duration of treatment: 5 days.

Administration in milk/milk replacer or directly in the mouth using either a syringe or an appropriate device for oral administration.

Recommended dosage: 7.5 ml of veterinary medicinal product/10 kg BW/day for 5 consecutive days, i.e. 105000 IU of paromomycin per kg BW/day for 5 consecutive days (i.e. approximately 150 mg paromomycin sulfate per kg BW/day).

In case of insufficient uptake of milk, the totality of the remaining solution should be administered orally directly into the mouth of the animal.

Pigs:

Colibacillosis

Duration of treatment: 3-5 days.

Administration in drinking water.

Recommended dosage: 1.25 – 2 ml of veterinary medicinal product/10 kg BW/day, equivalent to 17500 - 28000 IU of paromomycin per kg BW/day (i.e. approximately 25-40 mg paromomycin sulfate per kg BW/day).

For the administration through the drinking water the exact daily amount of veterinary medicinal product should be based on the number of the animals to be treated, and the recommended dose calculated according to the following formula:

ml product/ kg BW/day x Mean bodyweight (kg)

of animals to be treated ml product per litre

_ = drinking water/day/ animal/

Mean daily water consumption (litre) per animal

The uptake of medicated water depends on several factors including clinical conditions of the animals and the local conditions such as ambient temperature and humidity. In order to obtain the correct dosage, uptake of drinking water has to be monitored and the concentration of paromomycin has to be adjusted accordingly.

Medicated drinking water/milk/milk replacer and any stock solutions should be freshly prepared every 6 hours (in milk/milk replacer) or every 24 hours (in water).

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

After administration of 1X, 2X and 3X the recommended dose for the treatment of cryptosporidiosis (150, 300 and 450 mg of paromomycin sulfate/kg) during 3 times the recommended duration (15 days), in newborn calves (5-13 days) histopathological kidney abnormalities has been observed in some calves. These abnormalities can be observed in calves without any treatment however a nephrotoxicity related to the treatment cannot totally be ruled out.

At 3X the recommended dose, administration to newborn calves induced a slight loss of appetite, reversible at the end of the treatment period. The decrease of the milk consumption had a limited impact on the body weight gain.

At 5X the recommended dose, administration to newborn calves induced severe inflammation of the gastrointestinal tract and necrozing inflammation of the urinary bladder. Repeated overdose (at 5X) may be associated with death.

4.11 Withdrawal period(s)

Cattle (pre-ruminant cattle and newborn calves):

- Colibacillosis: Dosage:25-50 mg/kg/day for 3 to 5 days. Meat and offal: 20 days

- Cryptosporidiosis:Dosage: 150 mg/kg/day for 5 days. Meat and offal: 110 days

Pigs:

Meat and offal: 3 days

Due to the accumulation of paromomycin in the liver and kidneys, any repeated courses of treatment during the withdrawal period should be avoided.

5. PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: intestinal antiinfectives; antibiotics; paromomycin.

ATC vet code: QA07AA06.

5.1 Pharmacodynamic properties

Colibacillosis

Paromomycin belongs to the group of aminoglycoside antibiotics. Paromomycin changes the reading of messenger-RNA, which disrupts protein synthesis. The bactericidal activity of paromomycin is mainly attributed to its irreversible binding to ribosomes. Paromomycin has broad spectrum activity against numerous Grampositive and Gram-negative bacteria, including E. coli.

Paromomycin acts in a concentration-dependant manner. Five mechanisms of resistance have been identified: changes of the ribosomes due to mutations, reduction of permeability of bacterial cell wall or active efflux, enzymatic modification of ribosomes and inactivation of aminoglycosides by enzymes. The first three resistance mechanisms arise from mutations of certain genes on bacterial chromosome. The fourth and fifth resistance mechanism only occurs following uptake of mobile genetic elements coding for resistance. Paromomycin selects for resistance and cross-resistances at high frequency against a variety of other aminoglycosides among intestinal bacteria. Prevalence of resistance of E. coli to paromomycin was relatively stable between 2002 to 2015 and around 40% for bovine pathogens and 10% for porcine pathogens.

Cryptosporidiosis

Paromomycin has antiprotozoal activity, although its mechanism of action is unclear. In in vitro studies using HCT-8 and Caco-2 cell lines inhibitory activity against C. parvum was observed. Resistance of cryptosporidia to paromomycin has not been described to date. Nevertheless, the use of aminoglycosides is associated with the occurrence of bacterial resistance. Paromomycin may select for cross-resistance to other aminoglycosides.

5.2 Pharmacokinetic particulars

The bioavailability of paromomycin when administered as a single oral dose of 150 mg paromomycin/kg bodyweight to 8 - 10 days old calves was 3.23 %.

With regard to the absorbed fraction, the mean peak plasma concentration (C_max) was 4.148 ± 3.106 mg/l, the median time to attain the peak plasma concentration (T_max) was 4.75 hours (2-12 h) and the mean terminal half-life (t_1/2) was about 10 hours. The main part of the dose is eliminated unchanged in the faeces while the absorbed fraction is excreted almost exclusively in urine as unchanged paromomycin.

Paromomycin displays age-related pharmacokinetics, with the greatest systemic exposure occurring in newborn animals.

5.3 Environmental properties

The active ingredient paromomycin sulfate binds strongly to soil and is very persistent in the environment

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Benzyl alcohol (E1519)

Sodium metabisulfite (E223)

Disodium edetate

Purified water

6.2 Major 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 in 125 ml bottles:

1 year

Shelf-life of the veterinary medicinal product as packaged for sale in 250 ml bottles:

18 months

Shelf-life of the veterinary medicinal product as packaged for sale in 500 ml bottles:

2 years

Shelf-life of the veterinary medicinal product as packaged for sale in 1,000 ml bottles: 30 months

Shelf life after first opening the immediate packaging: 6 months.

Shelf life after reconstitution in drinking water: 24 hours

Shelf life after reconstitution in milk or milk replacer: 6 hours

6.4 Special precautions for storage

125 ml and 250 ml bottles: Do not store above 25°C

500 ml and 1000 ml bottles:

No special storage conditions required

All Presentations:

After first opening, keep the bottle tightly closed.

6.5 Nature and composition of immediate packaging

Nature of container

- White high density polyethylene bottles

- Polypropylene screw stopper equipped with a polyvinylchloride seal - Polypropylene dosing device of 30 ml graduated every 5 ml

Pack sizes:

Box containing 1 plastic bottle of 125 ml,

Box containing 1 plastic bottle of 250 ml

Box containing 1 plastic bottle of 500 ml

Box containing 1 plastic bottle of 1,000 ml

Plastic bottle of 125 ml

Plastic bottle of 250 ml

Plastic bottle of 500 ml

Plastic bottle of 1,000 ml

For each listed pack size, a dosing device is joined.

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

Ceva Animal Health Ltd

Explorer House

Mercury Park

Wycombe Lane

Wooburn Green

High Wycombe

Buckinghamshire

HP10 0HH

United Kingdom

8. MARKETING AUTHORISATION NUMBER

Vm 15052/5034

9. DATE OF FIRST AUTHORISATION

10 April 2018

10. DATE OF REVISION OF THE TEXT

February 2023

Approved : 24 February 2023