Milbactor Tablets for dogs weighing at least 5 kg

SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE VETERINARY MEDICINAL PRODUCT Milbactor 12.5 mg/125 mg tablets for dogs weighing at least 5 kg

2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet contains: Active substances: Milbemycin oxime 12.5 mg Praziquantel 125.0 mg Excipients: For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM Tablet. Yellowish-white with brown spots, round, slightly biconvex tablets.

4. CLINICAL PARTICULARS

4.1 Target species Dogs (weighing at least 5 kg).

4.2 Indications for use, specifying the target species In dogs: treatment of mixed infections by adult cestodes and nematodes of the following species: - Cestodes: Dipylidium caninum Taenia spp. Echinococcus spp. Mesocestoides spp. - Nematodes: Ancylostoma caninum Toxocara canis Toxascaris leonina Trichuris vulpis Crenosoma vulpis (Reduction of the level of infection) Angiostrongylus vasorum (Reduction of the level of infection by immature adult (L5) and adult parasite stages; see specific treatment and disease prevention schedules under section 4.9 “Amounts to be administered and administration route”) Thelazia callipaeda (see specific treatment schedule under section 4.9 “Amounts to be administered and administration route”) Revised: August 2021 AN: 02337/2020 and 02339/2020 Page 2 of 6 The product can also be used in the prevention of heartworm disease (Dirofilaria immitis) if concomitant treatment against cestodes is indicated.

4.3 Contraindications Do not use in dogs weighing less than 5 kg. Do not use in known cases of hypersensitivity to the active substances or to any of the excipients. See also point "Special precautions for use".

4.4 Special warnings for each target species Parasite resistance to any particular class of anthelmintic may develop following frequent, repeated use of an anthelmintic of that class. It is recommended to treat all the animals living in the same household concomitantly. In order to develop an effective worm control programme local epidemiological information and the risk of exposure of the dog should be taken into account and it is recommended to seek professional advice. When D. caninum infection is present, concomitant treatment against intermediate hosts, such as fleas and lice, should be considered to prevent re-infection.

4.5 Special precautions for use Special precautions for use in animals Studies with milbemycin oxime indicate that the margin of safety in certain dogs of Collie or related breeds is less than in other breeds. In these dogs, the recommended dose should be strictly observed. The tolerance of the product in young puppies from these breeds has not been investigated. Clinical signs in Collies are similar to those seen in the general dog population when overdosed (see in point 4.10). Treatment of dogs with a high number of circulating microfilariae can sometimes lead to the appearance of hypersensitivity reactions, such as pale mucous membranes, vomiting, trembling, laboured breathing or excessive salivation. These reactions are associated with the release of proteins from dead or dying microfilariae and are not a direct toxic effect of the product. The use in dogs suffering from microfilaremia is thus not recommended. In heartworm risk-areas, or in the case it is known that a dog has been travelling to and from heartworm risk regions, before using the product, a veterinary consultation is advised to exclude the presence of any concurrent infestation of Dirofilaria immitis. In the case of a positive diagnosis, adulticidal therapy is indicated before administering the product. No studies have been performed with severely debilitated dogs or individuals with seriously compromised kidney or liver function. The product is not recommended for such animals or only according to a benefit/risk assessment by the responsible veterinarian. Revised: August 2021 AN: 02337/2020 and 02339/2020 Page 3 of 6 In dogs less than 4 weeks old, tape worm infection is unusual. Treatment of animals less than 4 weeks old with a combination product may therefore not be necessary. Special precautions to be taken by the person administering the veterinary medicinal product to animals Wash hands after use. In the event of accidental ingestion of the tablets, particularly by a child, seek medical advice immediately and show the package leaflet or the label to the doctor. Other precautions Echinococcosis represents a hazard for humans. In case of Echinococcosis, specific guidelines on the treatment and follow-up and on the safeguard of persons have to be followed. Experts or institutes of parasitology should be consulted.

4.6 Adverse reactions (frequency and seriousness) On very rare occasions, systemic signs (such as lethargy), neurological signs (such as muscle tremors and ataxia) and/or gastrointestinal signs (such as emesis, diarrhoea, anorexia and drooling) have been observed in dogs after administration of the combination of milbemycin oxime and praziquantel. On very rare occasions hypersensitivity reactions have been observed following administration of the product. 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).

4.7 Use during pregnancy, lactation or lay The product may be used in breeding dogs including pregnant and lactating bitches.

4.8 Interaction with other medicinal products and other forms of interaction No interactions were observed when the recommended dose of the macrocyclic lactone selamectin was administered during treatment with the combination of milbemycin oxime and praziquantel at the recommended dose. In the absence of further studies, caution should be taken in the case of concurrent use of the product and other macrocyclic lactones. Also, no such studies have been performed with reproducing animals.

4.9 Amounts to be administered and administration route Oral use. Dogs should be weighed to ensure accurate dosing Minimum recommended dose rate: 0.5 mg of milbemycin oxime and 5 mg of praziquantel per kg are given once orally. Revised: August 2021 AN: 02337/2020 and 02339/2020 Page 4 of 6 The product should be administered with or after some food. Depending on the bodyweight of the dog, the practical dosing is as follows: Body weight Tablets 5 – 25 kg 1 tablet >25 – 50 kg 2 tablets >50 – 75 kg 3 tablets In cases when heartworm disease prevention is used and at the same time treatment against tapeworm is required, the product can replace the monovalent product for the prevention of heartworm disease. For treatment of Angiostrongylus vasorum infections, milbemycin oxime should be given four times at weekly intervals. It is recommended, where concomitant treatment against cestodes is indicated, to treat once with the product and continue with the monovalent product containing milbemycin oxime alone, for the remaining three weekly treatments. In endemic areas administration of the product every four weeks will prevent angiostrongylosis by reducing immature adult (L5) and adult parasite burden, where concomitant treatment against cestodes is indicated. For the treatment of Thelazia callipaeda, milbemycin oxime should be given in 2 treatments, seven days apart. Where concomitant treatment against cestodes is indicated, the product can replace the monovalent product containing milbemycin oxime alone.

4.10 Overdose (symptoms, emergency procedures, antidotes), if necessary No data available.

4.11 Withdrawal period(s) Not applicable.

5. PHARMACOLOGICAL PROPERTIES Pharmacotherapeutic group: Endectocides, Macrocyclic lactones ATCvet code: QP54AB51

5.1 Pharmacodynamic properties Milbemycin oxime belongs to the group of macrocyclic lactones, isolated from the fermentation of Streptomyces hygroscopicus var. aureolacrimosus. It is active against mites, against larval and adult stages of nematodes as well as against larvae of Dirofilaria immitis. The activity of milbemycin is related to its action on invertebrate neurotransmission: Milbemycin oxime, like avermectins and other milbemycins, increases nematode and insect membrane permeability to chloride ions via glutamate-gated chloride ion channels (related to vertebrate GABAA and glycine receptors). This leads to Revised: August 2021 AN: 02337/2020 and 02339/2020 Page 5 of 6 hyperpolarisation of the neuromuscular membrane and flaccid paralysis and death of the parasite. Praziquantel is an acylated pyrazino-isoquinoline derivative. Praziquantel is active against cestodes and trematodes. It modifies the permeability for calcium (influx of Ca2+) in the membranes of the parasite inducing an imbalance in the membrane structures, leading to membrane depolarisation and almost instantaneous contraction of the musculature (tetany), rapid vacuolization of the syncytial tegument and subsequent tegumental disintegration (blebbing), resulting in easier expulsion from the gastrointestinal tract or death of the parasite.

5.2 Pharmacokinetic particulars After oral administration of praziquantel in the dog, after a small amount of food, peak serum levels of parent are rapidly attained (Tmax approximately 0.25-2.5 hours) and decline quickly (t1/2 approximately 1 hour); there is a substantial hepatic first-pass effect, with very rapid and almost complete hepatic biotransformation, principally to monohydroxylated (also some di- and tri-hydroxylated) derivatives, which are mostly glucuronide and/or sulfate conjugated before excretion. Plasma binding is about 80%. Excretion is fast and complete (about 90% in 2 days); the principal route of elimination is renal. After oral administration of milbemycin oxime in dogs, after a small amount of food, peak plasma levels occur at about 0.75-3.5 hours, and decline with a half-life of the unmetabolised milbemycin oxime of 1-4 days. Bioavailability is about 80%. In the rat, metabolism appears to be complete although slow, since unchanged milbemycin oxime has not been found in urine or faeces. Main metabolites in the rat are monohydroxylated derivatives, attributable to hepatic biotransformation. In addition to relatively high liver concentrations, there is some concentration in fat, reflecting its lipophilicity.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients Cellulose, microcrystalline Lactose monohydrate Povidone Croscarmellose sodium Silica, colloidal anhydrous Meat Flavour Yeast powder Magnesium stearate

6.2 Major incompatibilities Not applicable.

6.3 Shelf life Shelf life of the veterinary medicinal product as packaged for sale: 3 years Revised: August 2021 AN: 02337/2020 and 02339/2020 Page 6 of 6

6.4 Special precautions for storage Store in the original package in order to protect from moisture. This veterinary medicinal product does not require any special temperature storage conditions.

6.5 Nature and composition of immediate packaging Blister packs consisting of cold formed OPA/Al/PVC foil and aluminium foil. Box with 1 blister of 4 tablets. Box with 12 blisters, each blister contains 4 tablets. 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. The product should not enter water courses as this may be dangerous for fish and other aquatic organisms.

7. MARKETING AUTHORISATION HOLDER KRKA, d.d., Novo mesto Šmarješka cesta 6 8501 Novo mesto Slovenia

8. MARKETING AUTHORISATION NUMBER Vm 01656/4074

9. DATE OF FIRST AUTHORISATION 29 December 2014

10. DATE OF REVISION OF THE TEXT August 2021 Approved: 20/08/21