4.1. Therapeutic indications

Cetraxal Plus is indicated in adults and in children aged 6 months and older for the following infections:

- Acute otitis externa (AOE)

- Acute otitis media in patients with tympanostomy tubes (AOMT)

caused by ciprofloxacin susceptible microorganisms (see sections 4.2, 4.4 and 5.1).

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2. Posology and method of administration

Posology

Adults and elderly population

Acute otitis externa and acute otitis media with tympanostomy tubes: Instil the contents of one single-dose container into the affected ear canal every 12 hours for 7 days.

No overall differences in safety and effectiveness have been observed between elderly and other adult patients.

Renal/ hepatic impairment

No dosage adjustment is deemed necessary.

Paediatric population

The dosage in children aged 6 months and older is the same as for adults for both indications.

Method of administration

Auricular use.

Precautions to be taken before handling or administering the medicinal product

The solution should be warmed before its use, by holding the bottle in the hand for several minutes. This will avoid the discomfort that may result from the instillation of a cold solution into the ear canal. The patient should lie with the affected ear upward and then for patients with otitis externa the drops should be instilled pulling several times on the auricle. For patients with acute otitis media with tympanostomy tubes, the tragus should be pumped 4 times by pushing inward to facilitate penetration of the drops into the middle ear. This position should be maintained for around 1 minute to facilitate penetration of the drops into the ear.

Repeat, if necessary, for the opposite ear.

4.3. Contraindications

Hypersensitivity to the active substances ciprofloxacin or fluocinolone acetonide or any member of the quinolone class of antimicrobial agents or to any of the excipients listed in section 6.1.

Viral infections of the external ear canal, including varicella and herpes simplex infections and fungal otic infections.

4.4. Special warnings and precautions for use

This medicinal product is for auricular use only, not for ophthalmic use, inhalation or injection. This medicine should not be swallowed or injected.

If otorrhea persists after a full course of therapy, or if two or more episodes of otorrhea occur within six months, further evaluation is recommended to exclude an underlying condition such as cholesteatoma, foreign body, or a tumour. If after the treatment some signs and symptoms persist, further evaluation is recommended to reassess the disease and the treatment.

Cetraxal Plus should be discontinued at the first appearance of a skin rash or any other sign of hypersensitivity. Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving systemic quinolones. Serious acute hypersensitivity reactions may require immediate emergency treatment.

As with other antibiotic preparations, the use of this product may result in overgrowth of non-susceptible organisms, including bacterial strains, yeast and fungi. If superinfection occurs, appropriate therapy should be initiated.

Some patients taking systemic quinolones have shown moderate to severe skin sensitivity to sun. Due to the site of administration, it is unlikely that this product may produce photoallergic reactions.

Corticosteroids may reduce resistance to, and aid in, the establishment of bacterial, viral, or fungal infections and mask the clinical signs of an infection, preventing recognition of ineffectiveness of the antibiotic, or may suppress hypersensitivity reactions to substances in the product.

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

Paediatric population

Safety and efficacy of Cetraxal Plus have not been established in children younger than 6 months. Under exceptional circumstances, Cetraxal Plus treatment could be used in this sub-paediatric population after a very careful benefit/risk evaluation by the prescribing physician taking into account that although there are no known safety concerns or differences in disease process to preclude use in these children, clinical experience is insufficient in these specific subgroups of paediatric population.

4.5. Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed with Cetraxal Plus. However, due to negligible plasma levels observed after application in the ear (see section 5.2), it is unlikely that ciprofloxacin or fluocinolone acetonide may show clinically meaningful systemic interaction with other drugs.

The systemic administration of some quinolones has been shown to enhance the effects of the oral anticoagulant, warfarin, and its derivatives, and has been associated with transient elevations in serum creatinine in patients receiving cyclosporine concomitantly.

Oral administration of ciprofloxacin has been shown to inhibit cytochrome P450 CYP1A2 and CYP3A4 isozymes, and alter the metabolism of methylxanthine compounds (caffeine, theophylline). Following topical otic administration of Cetraxal Plus, ciprofloxacin plasma concentrations are low, and it is unlikely that an interaction involving P450 metabolism with concomitant medications would result in clinically relevant changes in plasma levels of methylxanthine compounds.

It is recommended not to use other ear preparations concomitantly. If more than one medicine needs to be administered by this route, it is advised to administer them apart.

4.6. Fertility, pregnancy and lactation

Pregnancy

Data available on administration of ciprofloxacin to pregnant women indicates no malformative or foeto/neonatal toxicity. Since systemic exposure to ciprofloxacin will be very low no effects are anticipated on the foetus. Corticosteroids have been shown to be teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Some corticosteroids have been shown to be teratogenic after dermal application in laboratory animals. There are no adequate and well-controlled studies in pregnant women on teratogenic effects from fluocinolone acetonide.

Before administering the medicine, an assessment should be made on the benefits of the treatment outweighing the possible risk.

Breastfeeding

Ciprofloxacin is excreted in breast milk. Since systemic exposure to ciprofloxacin will be very low no effects are anticipated on the children that are breastfeeding.

Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects.

It is not known whether topical administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk.

Caution should be exercised when Cetraxal Plus is administered to a nursing woman.

Fertility

No animal studies have been performed to evaluate the effect on fertility of Cetraxal Plus.

4.7. Effects on ability to drive and use machines

Cetraxal Plus has no influence on the ability to drive and use machines due to the route of administration and the conditions of use.

4.8. Undesirable effects

Tabulated summary of adverse events

The following adverse reactions listed in the table below were observed in clinical studies or with post-marketing experience. They are ranked according to system organ class and classified according to the following convention: very common (≥ 1/10), common (≥ 1/100 to <1/10), uncommon (≥ 1/1000 to <1/100), rare (≥ 1/10,000 to <1/1000), very rare (<1/10,000), or not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

System Organ Classification

MedDRA Preferred Term

Infections and infestations

Uncommon: candidiasis, ear infection fungal, contralateral otitis media

Nervous system disorders

Common: dysgeusia

Uncommon: paraesthesia (tingling in ears), dizziness, headache, crying

Ear and labyrinth disorders

Common: ear pain, ear discomfort, ear pruritus

Uncommon: hypoacusis, tinnitus, otorrhoea, ear congestion, tympanic membrane disorder, auricular swelling

Eye disorders

Not known: Vision, blurred (see also section 4.4)

Vascular disorders

Uncommon: flushing

Gastrointestinal disorders

Uncommon: vomiting

Skin and subcutaneous tissue disorders

Uncommon: skin exfoliation, rash erythematous, rash, granulation tissue

General disorders and administration site conditions

Uncommon: irritability, fatigue

Investigations

Uncommon: medication residue

Injury, poisoning and procedural complications

Uncommon: device occlusion (tympanostomy tube obstruction)

Description of selected adverse reactions

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving systemic quinolone therapy. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, angioedema (including laryngeal, pharyngeal or facial oedema), airway obstruction, dyspnoea, urticaria, and itching.

Ruptures of the shoulder, hand, Achiles or other tendons that required surgical repair or resulted in prolonged disability have been reported in patients receiving systemic fluoroquinolones. Studies and post marketing experience with systemic fluoroquinolones indicate that the risk of these ruptures may be increased in patients receiving corticosteroids, especially geriatric patients and in tendons under high stress, including the Achiles tendon. To date, clinical and post marketing data have not demonstrated a clear association between otic administration of ciprofloxacin and these musculoskeletal and connective tissue adverse reactions.

Paediatric population

Cetraxal Plus has been shown to be safe in paediatric patients 6 months of age or older.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme (website: www.mhra.gov.uk/yellowcard) or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

No case of overdose has been reported.

Due to negligible plasma levels observed after application in the ear, it is unlikely that topically applied ciprofloxacin or fluocinolone acetonide may show clinically meaningful systemic effects. Acute overdosage is very unlikely to occur, however, in the case of chronic overdosage or misuse, the features of hypercortisolism may appear.

The limited holding capacity of the ear canal for topical otic products practically precludes overdosing via the ototopical route. However, oral ingestion of Cetraxal Plus resulting in overdose or long-term ototopical therapy may produce suppression of the hypothalamic-pituitary-adrenal (HPA) axis. Although decreases in paediatric growth velocity and/or suppression of cortisol plasma concentrations may be more pronounced after substantial overdose or prolonged treatment (e.g. several months) with Cetraxal Plus, the effect is expected to be transient (days to weeks) and easily reversible with no long-term sequelae.

If the preparation is accidentally swallowed, treatment will include gastric emptying by induced vomiting or gastric lavage, the administration of activated charcoal and antacids containing magnesium or calcium.

Further management should be as clinically indicated or as recommended by the national poisons centre, where available.