SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

TOBRAVISC, 3.0 mg/ml eye drops, solution

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml solution contains 3 mg tobramycin.

Preservative: benzododecinium bromide (BDAB)

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Eye drops, solution.

Clear, colourless solution.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Treatment of superficial bacterial infections of the eye, such as conjunctivitis, caused by tobramycin susceptible/suspected susceptible bacteria in adults and children aged 1 year and older.

4.2 Posology and method of administration

The dose is one drop of TOBRAVISC eye drops into the conjunctival sac two times daily (morning and evening) for 7±1 days. If severe disease: on the first day, four instillations while awake. Thereafter instil one drop in each eye twice a day, while awake, until completion of the 7±1 days-total treatment period.

Method of Administration

For ocular use only.

Nasolacrimal occlusion or gently closing the eyelid after administration is recommended. This may reduce the systemic absorption of medicinal products administered via the ocular route and result in a decrease in systemic adverse reactions.

To prevent contamination of the dropper tip and solution, care must be taken not to touch the eyelids, surrounding areas, or other surfaces with the dropper tip of the bottle. Keep the bottle tightly closed when not in use.

After cap is removed, if the tamper evident snap collar is loose, remove before using the product.

In case of concomitant therapy with other topical ocular medicines, an interval of 5-10 minutes should be allowed between successive applications.

Use in elderly

No dosage adjustment in elderly patients is necessary.

Paediatric Population

TOBRAVISC eye drops may be used in children 1 year of age and older at the same dose as in adults. Currently available data is described in Section 5.1. The safety and efficacy in children younger than 1 year of age have not been established, and no data are available.

Use in hepatic and renal impairment

Ocular application of tobramycin gives very little systemic exposure. In case of concomitantly administered systemic treatment with aminoglycoside antibiotics, care should be taken to monitor the total serum concentration in order to ensure that an appropriate therapeutic level is maintained.

4.3 Contraindications

Hypersensitivity to the active substance or any of the excipients listed in section 6.1.

4.4    Special warnings and precautions for use

For ocular use only. Not for injection or ingestion.

Sensitivity to topically administered aminoglycosides may occur in some patients. Severity of hypersensitivity reactions may vary from local effects to generalized reactions such as erythema, itching, urticarial, skin rash, anaphylaxis, anaphylactoid reactions, or bullous reactions. If hypersensitivity develops during the use of this medicine, treatment should be discontinued.

Cross-hypersensitivity to other aminoglycosides can occur, and the possibility that patients who become sensitized to topical ocular tobramycin may also be sensitive to other topical and/or systemic aminoglycosides should be considered.

Serious adverse reactions including neurotoxicity, ototoxicity and nephrotoxicity have occurred in patients receiving systemic tobramycin therapy. Caution is advised when used concomitantly with aminoglycosides.

As with other antibiotic preparations, prolonged use of TOBRAVISC may result in overgrowth of non-susceptible organisms, including fungi. If superinfection occurs, appropriate therapy should be initiated.

Contact lens wear is not recommended during treatment of an ocular infection. Therefore, patients should be advised not to wear contact lenses during treatment with the product.

Additionally, this product contains benzododecinium bromide which may cause irritation and is known to discolour soft contact lenses. Avoid contact with soft contact lenses. Patients must be instructed to remove contact lenses prior to application of TOBRAVISC and wait 15 minutes after instillation of the dose before reinsertion.

4.5    Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

Topical corticosteroids, when used in combination with tobramycin 3 mg/ml, may mask the clinical signs of bacterial, fungal, or viral infections and may suppress hypersensitivity reactions.

If more than one topical ophthalmic medicinal product is being used, the medicines must be administered at least 5 minutes apart. Eye ointments should be administered last.

4.6 Fertility, pregnancy and lactation

Fertility

Studies have not been performed to evaluate the effect of topical ocular administration of TOBRAVISC on human fertility

Pregnancy

There are no or limited amount of data from the use of topical ocular tobramycin in pregnant women. Tobramycin does cross the placenta into the fetus after intravenous dosing in pregnant women. Tobramycin is not expected to cause ototoxicity from in utero exposure.

Studies in animals have shown reproductive toxicity at dosages considered sufficiently in excess of the maximal human dose derived from Tobramycin Eye Drops/Ointment so as to have limited clinical relevance. Tobramycin has not been shown to induce teratogenicity in rats or rabbits (See Section 5.3).

Tobravisc should be used during pregnancy only if clearly needed.

Breastfeeding

Tobramycin is excreted in human milk after systemic administration. It is unknown whether tobramycin is excreted in human milk following topical ocular administration. It is not likely that the amount of Tobramycin would be detectable in human milk or be capable of producing clinical effects in the infant following topical use of the product. However, a risk to the suckling child cannot be excluded. A decision should be made whether to discontinue breastfeeding or to discontinue/abstain from TOBRAVISC therapy taking into account the benefit of breastfeeding for the child and benefit of therapy for the woman.

4.7 Effects on ability to drive and use machines

TOBRAVISC has no or negligible influence on the ability to drive and use machines. Temporary blurred vision or other visual disturbances may affect the ability to drive or use machines. If blurred vision occurs at instillation, the patient must wait until the vision clears before driving or using machinery.

4.8 Undesirable effects

Summary of the safety profile

In clinical trials the most frequently reported adverse reactions were ocular hyperaemia and ocular discomfort, occurring in approximately 1.4% and 1.2% of patients.

The following adverse reactions are classified according to the following convention: very common (> 1/10), common (> 1/100 to <1/10), uncommon (>1/1,000 to <1/100), rare (>1/10,000 to <1/1,000), very rare (<1/10,000), or not known (cannot be estimated from the available data). Within each frequency-grouping, adverse reactions are presented in order of decreasing seriousness. The adverse reactions were obtained from clinical trials and postmarketing spontaneous reports. The following adverse reactions were observed following ophthalmic use of TOBRAVISC:

System Organ Classification	MedDRA Preferred Term (v. 15.1)
Immune system disorders	Uncommon: Hypersensitivity Not known: Anaphylactic reaction
Nervous system disorders	Uncommon: Headache
Eye disorders	Common: Ocular discomfort, Ocular hyperaemia, Eye allergy, Eyelids pruritus

System Organ Classification	MedDRA Preferred Term (v. 15.1)
	Uncommon: Keratitis, Corneal abrasion, Visual impairment, Vision blurred, Erythema of eyelid, Eye discharge, Conjunctival oedema, Eyelid oedema, Eye pain, Dry eye, Eye pruritus, Lacrimation increased
	Not known: Eye irritation
Skin and Subcutaneous Tissue Disorders	Uncommon: Urticaria, Dermatitis, Madarosis, Leukoderma, Pruritus, Dry skin
	Not known: Stevens-Johnson syndrome, rash, erythema multiforme

Description of selected adverse events

Serious adverse reactions including neurotoxicity, ototoxicity and nephrotoxicity have occurred in patients receiving systemic tobramycin therapy (See Section 4.4 special warnings and precautions for use).

Sensitivity to topically administered aminoglycosides may occur in some patients (See Section 4.4 special warnings and precautions for use).

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 at www.mhra.gov.uk/yellowcard.

4.9 Overdose

Due to the characteristics of this preparation, no toxic effects are to be expected with an ocular overdose of this product, or in the event of accidental ingestion of the contents of one bottle or tube.

Clinically apparent signs and symptoms of an overdose of TOBRAVISC (punctate keratitis, erythema, increased lacrimation, oedema, and lid itching) may be similar to adverse reaction effects seen in some patients.

A topical overdose of TOBRAVISC may be flushed from the eye(s) with lukewarm water.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic Group: ophthalmologicals; anti-infectives ATC code: S01A A12

Mode of Action

The preparation contains tobramycin, a rapidly bactericidal aminoglycoside antibiotic. It exerts its primary effect on bacterial cells by inhibiting polypeptide assembly and synthesis on the ribosome.

Mechanism of resistance

Resistance to tobramycin occurs by several different mechanisms including (1) alterations of the ribosomal subunit within the bacterial cell; (2) interference with the transport of tobramycin into the cell, and (3) inactivation of tobramycin by an array of adenylating, phosphorylating, and acetylating enzymes. Genetic information for production of inactivating enzymes may be carried on the bacterial chromosome or on plasmids. Cross resistance to other aminoglycosides may occur.

Breakpoints

The breakpoints and the in vitro spectrum as mentioned below are based on systemic use. These breakpoints might not be applicable on topical ocular use of the medicinal product as higher concentrations are obtained locally and the local physical/chemical circumstances can influence the activity of the product on the site of administration. In accordance with EUCAST, the following breakpoints are defined for tobramycin:

The information listed below gives only an approximate guidance on probabilities whether microorganisms will be susceptible to tobramycin in TOBRAVISC. Bacterial species that have been recovered from external ocular infections of the eye such as observed in conjunctivitis are presented here.

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of tobramycin in at least some types of infections is questionable.

Paediatric Population

Over 600 paediatric patients were enrolled in 10 clinical studies with tobramycin eye drops or eye ointment for the treatment of bacterial conjunctivitis, blepharitis or blepharoconjunctivitis. These patients ranged in age from 1 year to 18 years. Overall the safety profile in paediatric patients was comparable to that of adult patients. For children younger than age 1, no recommendation on a posology can be made due to a lack of data.

5.2    Pharmacokinetic properties

Tobramycin is poorly absorbed across the cornea and conjunctiva and minimal amounts are absorbed into the eye after topical administration of tobramycin

5.3    Preclinical safety data

Tobramycin is very poorly absorbed from the gastrointestinal tract. High, parenterally administered doses of tobramycin have been reported to cause renal toxicity in rats and dogs, and ototoxicity in cats.

Preclinical studies have shown high systemic doses of tobramycin were administered using the intra-peritoneal (IP) route at 30 and 60 mg/kg to rats during periods of major organogenesis; which caused increases in glomerular density and the loss of cortical area within the kidney in the fetuses and in newborn rats. Similarly in other laboratory animals, aminoglycoside antibiotics are considered to be ototoxic. Prolonged systemic treatment of tobramycin in cats administered using the subcutaneous route at 20, 40 and 80 mg/kg/day for 30 weeks resulted in dose-dependent degeneration of hair cells and supporting sensory structures in the ear.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Xanthan gum

Benzododecinium bromide (BDAB)

Mannitol Trometamol Boric acid Polysorbate 80

Sulphuric acid and/or sodium hydroxide (to adjust pH) Purified water

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

2 years.

Discard four weeks after first opening.

6.4    Special precautions for storage

No special precautions for storage.

Nature and contents of container

TOBRAVISC eye drops is supplied in 5 ml opaque low-density polyethylene bottles with polypropylene screw caps (DROPTAINER).

6.6 Special precautions for disposal

No special requirements.

7    MARKETING AUTHORISATION HOLDER

Alcon Laboratories (UK) Ltd Frimley Business Park,

Frimley, Camberley,

Surrey, GU16 7SR,

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 00649/0172

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

16/04/2010

10    DATE OF REVISION OF THE TEXT

29/09/2016