4.1. Therapeutic indications

Ciprofloxacin/Dexamethasone is indicated for the treatment of the following infections in adults and children (see section 4.2). See section 5.1 for commonly susceptible species.

• Acute otitis externa (AOE)

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

Instil four drops in the affected ear(s) twice a day for 7 days according to the different instillation instructions for patients with acute otitis externa.

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

Paediatric population

This medicine has been shown to be safe and effective in paediatric patients 1 year of age and older for the treatment of AOE. This medicine can be used at the same dose as in adults (see Section 5.2).

Patients with hepatic and renal impairment

Hepatic or renal impairment (mild to moderate) does not alter the pharmacokinetics of ciprofloxacin or dexamethasone following systemic administration.

Following topical otic administration of ciprofloxacin/dexamethasone ear drops, suspension, small increases in ciprofloxacin and dexamethasone plasma concentrations may be observed in patients with severe renal or hepatic impairment. However, since systemic exposure to ciprofloxacin or dexamethasone is low after topical otic administration, any increase in systemic concentrations due to renal or hepatic dysfunction would still be well below plasma concentrations that are well tolerated in children or adults following oral or intravenous recommended doses.

Dose adjustment of this medication in patients with renal or hepatic dysfunction is not necessary.

Method of administration

For otic use only.

Instruct the patients to shake the bottle well before use. The suspension should be warmed by holding the bottle in the hand for several minutes to avoid dizziness, which may result from the instillation of a cold suspension. The patient should lie with the affected ear upward, and then the drops should be instilled pulling several times on the aurical. This position should be maintained for around 5 minutes to facilitate penetration of the drops in the ear. Repeat, if necessary, for the opposite ear.

To prevent contamination of the dropper tip in order to limit bacterial risks, care should be taken not to touch the auricle or the external ear canal and surrounding areas, or other surfaces with the dropper tip of the bottle. Keep the bottle tightly closed when not in use. Keep the bottle until the completion of the treatment.

4.3. Contraindications

Hypersensitivity to ciprofloxacin, to other quinolones, to dexamethasone or to any of the excipients listed in section 6.1.

Viral (i.e., varicella, herpes simplex) and fungal otic infections.

4.4. Special warnings and precautions for use

This medicinal product is for otic use only, not for ophthalmic use, inhalation or injection.

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.

As with other antibacterial preparations, prolonged use of this product may result in overgrowth of non-susceptible organisms, including bacterial strains, yeast and fungi. If superinfection occurs, discontinue use and appropriate therapy should be initiated. If after one week of therapy some signs and symptoms persist, further evaluation is recommended to reassess the disease and the treatment.

Serious and occasionally fatal hypersensitivity (anaphylactic) reactions, some following the first dose, have been reported in patients receiving systemic quinolones. Some reactions were accompanied by cardiovascular collapse, loss of consciousness, angioedema (including laryngeal, pharyngeal or facial edema), airway obstruction, dyspnea, urticaria and itching. This product should be discontinued at the first appearance of a skin rash or any other sign of hypersensitivity. Serious acute hypersensitivity reactions may require immediate emergency treatment. Oxygen and airway management should be administered as clinically indicated.

Tendon inflammation and rupture may occur with systemic fluoroquinolone therapy including ciprofloxacin, particularly in elderly patients and in those treated currently with corticosteroids.

Therefore treatment with this medicine should be discontinued at the first sign of tendon inflammation.

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.

Benzalkonium chloride may irritate the skin.

Paediatric population

Safety and efficacy of ciprofloxacin/dexamethasone have not been established in children younger than 1 year in acute otitis externa. Under exceptional circumstances, ciprofloxacin/dexamethasone 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.

Following topical otic administration in paediatric patients with patent tympanostomy tubes, low plasma concentrations were observed for ciprofloxacin (≥ 0.50 ng/ml in only 4 of 25 patients) and for dexamethasone (≥ 0.05 ng/ml in 14 of 24 patients) at 6 hours post-dose. It is concluded that clinically relevant drug-drug pharmacokinetic interactions for ciprofloxacin or dexamethasone through protein binding, or involving P450 metabolism with concomitant medications, would be unlikely for both compounds following topical otic administration.

However, 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 ciprofloxacin/dexamethasone ear drops, suspension, 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.

4.6. Fertility, pregnancy and lactation

Pregnancy

Since no animal reproduction studies and no adequate or well controlled studies in pregnant women have been conducted with the combination of ciprofloxacin and dexamethasone, this medicine should not be used during pregnancy unless clearly necessary and only if the potential benefit justifies the potential risk to the foetus (see Section 5.3).

Breast-feeding

Ciprofloxacin and corticosteroids, as a class, appear in milk following oral administration. It is not known whether topical administration to humans could result in sufficient systemic absorption to produce detectable quantities in breast milk. A risk to the suckling child cannot be excluded. Caution should be exercised if this medicine is administered during lactation.

Fertility

No human data on the effect of ciprofloxacin/dexamethasone on fertility are available (see also section 5.3).

Topical dermal studies in animals have shown effects on male sex organs following long-term use of dexamethasone at high doses. Reproduction studies performed in rats and mice at doses up to six-times the usual daily human oral dose revealed no evidence of impaired fertility.

4.7. Effects on ability to drive and use machines

This medicine has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Summary of the safety profile

In 5 clinical studies involving 976 patients, ciprofloxacin/dexamethasone was administered twice daily. This included 439 patients participating in 3 clinical studies with acute otitis media with tympanostomy tubes and 537 patients participating in 2 clinical studies with acute otitis externa. No serious otic or systemic undesirable effects related to ciprofloxacin/dexamethasone were reported in any of the clinical studies. In clinical trials, the most common adverse drug reactions were ear pain and ear discomfort, occurring approximately 1% to 1.5% patients.

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

Adverse reactions

Eye disorders

Not known: vision blurred (see section 4.4.)

Infections and Infestations

Uncommon: candidiasis

Immune system disorders

Not known: hypersensitivity

Nervous System Disorders

Uncommon: paraesthesia (tingling in ears), Crying

Rare: dizziness, headache

Ear and Labyrinth Disorders

Common: ear pain

Uncommon: otorrhoea, ear congestion, ear discomfort, ear pruritus, ear infection fungal,

Rare: hypoacusis, tinnitus, medication residue present

Not known: auricular swelling

Vascular Disorders

Uncommon: flushing

Gastrointestinal Disorders

Uncommon: vomiting, dysgeusia

Skin and Subcutaneous Tissue Disorders

Uncommon: skin exfoliation

Rare: rash erythematous

General Disorders and Administration Site Conditions

Uncommon: device occlusion (tympanostomy tube obstruction), irritability, fatigue

Description of selected adverse reactions

The most frequently reported adverse reaction reported in the 537 patients with acute otitis externa was ear pruritus (1.5%). No patient discontinued therapy due to an occurrence of ear pruritus.

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.

The development of secondary infections has occurred after the use of combinations containing corticosteroids or antimicrobials.

Ruptures of the shoulder, hand, Achilles, 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 Achilles 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

Ciprofloxacin/dexamethasone has been shown to be safe in paediatric patients 1 year of age or older for the treatment of AOE. The frequency, type and severity of adverse reactions in paediatric patients are expected to be the same as in adults.

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 the Yellow Card Scheme (www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store).

4.9. Overdose

The limited holding capacity of the ear canal for topical otic products practically precludes overdosing via the ototopical route. However, oral ingestion of this medicine 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 this medicine, the effect is expected to be transient (days to weeks) and easily reversible with no long-term sequelae.

Treatment of acute overdosage is generally by supportive and systemic therapy, and may initially include emesis and gastric lavage.