Neptra - summary of medicine characteristics

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

• 1. NAME OF THE VETERINARY MEDICINAL PRODUCT

Neptra ear drops solution for dogs

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

1 dose (1 ml) contains:

Active substances:

Florfenicol: 16.7 mg

Terbinafine hydrochloride: 16.7 mg, equivalent to terbinafine base: 14.9 mg

Mometasone furoate: 2.2 mg

Excipients:

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Ear drops, solution.

Clear, colourless to yellow, slightly viscous liquid.

4. CLINICAL PARTICULARS4.1 Target species

Dogs

• 4.2 Indications for use, specifying the target species

For the treatment of acute canine otitis externa or acute exacerbations of recurrent otitis caused by mixed infections of susceptible strains of bacteria sensitive to florfenicol (Staphylococcus pseudintermedius ) and fungi sensitive to terbinafine (Malassezia pachydermatis ).

4.3 Contraindications

Do not use in case of hypersensitivity to the active substances, to other corticosteroids or to any of the excipients.

Do not use if the ear drum is perforated.

Do not use in dogs with generalised demodicosis.

Do not use in pregnant or breeding animals.

• 4.4 Special warnings for each target species

Bacterial and fungal otitis is often secondary to other conditions. In animals with a history of recurrent otitis externa, the underlying causes of the condition such as allergy or anatomical conformation of the ear must be addressed in order to avoid ineffective treatment with a veterinary medicinal product.

In cases of parasitic otitis, an appropriate acaricidal treatment should be implemented.

Ears must be cleaned before administration of the product. It is recommended not to repeat ear cleaning until 28 days after administration of the product. In clinical trials, only saline was used for ear cleaning before treatment initiation with the veterinary medicinal product.

This combination is intended for the treatment of acute otitis when mixed infections caused by Staphylococcus pseudintermedius susceptible to florfenicol and Malassezia pachydermatis susceptible to terbinafine have been demonstrated.

• 4.5 Special precautions for use

Special precautions for use in animals

The safety of the veterinary medicinal product has not been established in dogs less than 3 months of age. Target animal safety was not studied in dogs under 4 kg bodyweight. However, no safety issues were identified in field studies in dogs weighing less than 4kg.

Before the veterinary medicinal product is applied, the external auditory canal must be examined thoroughly to ensure that the ear drum is not perforated.

Re-evaluate the dog if hearing loss or signs of vestibular dysfunction are observed during treatment.

After the administration, wet ears or clear discharge can be observed which is not related to the disease pathology.

Whenever possible, the use of the veterinary medicinal product should be based on identification of infecting organisms and susceptibility testing.

Use of the veterinary medicinal product deviating from the instructions given in the Summary of Product Characteristics (SPC) may increase the prevalence of bacteria resistant to florfenicol and fungi resistant to terbinafine and may decrease the effectiveness of treatment with other antibiotics and antifungal agents.

Decreased cortisol levels were observed after product instillation in tolerance studies (before and after ACTH stimulation), indicating that mometasone furoate is absorbed and enters the systemic circulation. The main findings observed at the 1X dose were decreases in cortical response to ACTH stimulation, decreased absolute lymphocyte and eosinophil counts, and decreased adrenal weight. Prolonged and intensive use of topical corticosteroid preparations is known to trigger systemic effects, including suppression of adrenal function (see section 4.10).

If hypersensitivity to any of the components occurs, the ear should be thoroughly washed. Additional corticosteroid treatments should be avoided.

Use with caution in dogs with a suspected or confirmed endocrine disorder (e.g., diabetes mellitus, hypo- or hyperthyroidis­m, etc.).

Caution should be taken to prevent the veterinary medicinal product from getting into the eyes of the dog being treated e.g. by restraining the dog’s head to prevent shaking (see section 4.9). In case of exposure to the eye, rinse with plenty of water.

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

The veterinary medicinal product has serious eye irritation potential. Accidental eye exposure may occur when the dog shakes its head during or just after administration. To avoid this risk for the owners, it is recommended that this veterinary product is administered only by veterinarians or under their close supervision. Appropriate measures (e.g. wearing safety glasses during administration, massaging the ear canal well after administration to ensure even distribution of product, restraining the dog after administration) are needed to avoid exposure to the eyes. In case of accidental ocular exposure, flush the eyes thoroughly with water for 10 to 15 minutes. If symptoms develop, seek medical advice and show the package leaflet or the label to the physician.

Although no potential for skin irritation was indicated by experimental studies, contact of the product with the skin should be avoided. In case of accidental skin contact, wash exposed skin thoroughly with water.

May be harmful after ingestion. Avoid ingestion of the product including hand-to-mouth exposure. In case of accidental ingestion seek medical advice immediately and show the package leaflet or the label to the physician.

• 4.6 Adverse reactions (frequency and seriousness)

Vocalisation, head shaking and application site pain shortly after product application have been reported very rarely in spontaneous (pharmacovigilance) reports. Ataxia, internal ear disorder, nystagmus, emesis, application site erythema, hyperactivity, anorexia and application site inflammation and eye disorders (such as eye irritation, blepharospasm, conjunctivitis, corneal ulcer, keratoconjuncti­vitis sicca) were reported very rarely in spontaneous (pharmacovigilance) reports.

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 safety of the veterinary medicinal product has not been established during pregnancy and lactation. Do not use during pregnancy and lactation.

Studies to determine the effect on fertility in dogs have not been conducted. Do not use in breeding animals.

4.8 Interaction with other medicinal products and other forms of interaction

None known.

Compatibility with ear cleaners, other than saline solution, has not been demonstrated.

• 4.9 Amounts to be administered and administration route

Auricular use.

Single treatment.

The recommended dosage is 1 single-dose container (i.e. 1 ml of solution) per infected ear.

The maximum clinical response may not be seen until 28 days after administration.

Shake well before use for 5 seconds.

Clean and dry the external ear canal before administering the product.

While holding the single-use container in an upright position, remove the cap.

Use the upper end of the cap to completely break the seal and then remove cap from the single-use container.

Screw the applicator nozzle onto the single-use container.

Insert the applicator nozzle into the affected external ear canal and squeeze the entire contents into the ear.

Gently massage the base of the ear for 30 seconds to allow distribution of the solution. Restrain the dog’s head to prevent shaking, for 2 minutes.

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

Auricular administration of up to five times the recommended dose at biweekly intervals for a total of three treatments was generally well tolerated.

The most prominent effects were consistent with glucocorticoid administration; specific observations included suppression of the adrenal cortical response to ACTH-stimulation, decreased adrenal weight and atrophy of the adrenal cortex, decreased absolute lymphocyte and eosinophil counts, increased absolute neutrophil count, increased liver weight with hepatocellular enlargement/cy­toplasmic change, and decreased thymus weight. Other potentially treatment-related effects included mild changes to aspartate aminotransferase (AST), total protein, cholesterol, inorganic phosphorus, creatinine and calcium. After 3 weekly administrations of up to 5× the recommended posology, the test product induced slight erythema in one or both ears that returned to normal within 48 hours.

• 4.11 Withdrawal period(s)

Not applicable.

5. PHARMACOLOGICAL PROPERTIES

Pharmacotherapeutic group: Otologicals/Cor­ticosteroids and anti-infectives in combination. ATCvet code: QS02CA91

5.1 Pharmacodynamic properties

The veterinary medicinal product is a fixed combination of three active substances (corticosteroid, antifungal and antibiotic).

Mometasone furoate is a corticosteroid with high potency. Like other corticosteroids, it has antiinflammatory and anti-pruritic properties.

Terbinafine hydrochloride is an allylamine with a pronounced fungicidal activity. It selectively inhibits the early synthesis of ergosterol, which is an essential component of the membrane of yeasts and fungi including Malassezia pachydermatis (MIC90 of 1 ^g/ml). Terbinafine hydrochloride has a different mode of action to azole antifungals, therefore there is no cross-resistance with azole antifungals. Decreased in vitro susceptibility to terbinafine has been reported for strains of Malassezia pachydermatis which form biofilms.

Florfenicol is a bacteriostatic antibiotic which acts by inhibiting protein synthesis, through binding to and acting on the 50S ribosomal subunit of bacteria. Its spectrum of activity includes Gram-positive and Gram-negative bacteria including Staphylococcus pseudintermedius (MIC90 of 2 ^g/ml). In vitro activity of florfenicol against Pseudomonas spp. is low (MIC90 > 128 ^g/ml).

Florfenicol resistance genes detected in staphylococci include cfr and fexA. Cfr modifies the RNA in the drug binding site (causing reduced affinity to chloramphenicol, florfenicol and clindamycin) and the cfr gene can be present in plasmids or other transmissible elements. FexA codes for a membrane associated efflux system (affecting both florfenicol and chloramphenicol efflux) and is found in chromosomes as well as in plasmids.

• 5.2 Pharmacoki­netic particulars

Systemic absorption of the three active substances was determined after single co-administration into one ear canal of healthy beagle dogs. Mean peak plasma concentrations (Cmax) were low with 1.73 ng/ml florfenicol, 0.35 ng/ml mometasone furoate and 7.83 ng/ml terbinafine HCl reached at the tmax of 24 h, 0.5 h and 20 h after treatment, respectively.

The extent of transcutaneous absorption of topical medications is determined by many factors including the integrity of the epidermal barrier. Inflammation can increase the transcutaneous absorption of veterinary medicinal products across the skin adjacent to the external opening of the ear canal.

6. PHARMACEUTICAL PARTICULARS6.1 List of excipients

Propylene carbonate

Propylene glycol

Ethanol (96 per cent)

Macrogol 8000

Water, purified

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: 18 months

6.4. Special precautions for storage

Do not store above 25°C.

• 6.5 Nature and composition of immediate packaging

Single-use sealed laminated tube containing 1 ml solution, with polypropylene cap and separate LDPE applicator nozzle packed in a transparent plastic blister.

Carton containing 1, 2, 10 or 20 blisters.

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

7. MARKETING AUTHORISATION HOLDER

Bayer Animal Health GmbH

51368 Leverkusen

Germany

8. MARKETING AUTHORISATION NUMBER(S)

EU/2/19/246/001 (2 tubes)

EU/2/19/246/002 (10 tubes)

EU/2/19/246/003 (20 tubes)

EU/2/19/246/004 (1 tube)

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 10 December 2019.