TOBRAVISC, 3.0 mg/ml eye drops, solution

1 ml solution contains 3 mg tobramycin.

For a full list of excipients, see section 6.1.

Eye drops, solution.

Clear, colourless solution.

Treatment of superficial bacterial infections of the eye, such as conjunctivitis, caused by tobramycin susceptible/suspected susceptible bacteria.

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.

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.

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.

Use in children and adolescents

TOBRAVISC eye drops may be used in paediatric patients (1 year of age and older) at the same dose as in adults. However, limited information is available in paediatric patients.

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.

Hypersensitivity to tobramycin, any other aminoglycosides, or any of the excipients

• For topical ophthalmic use only. Not for injection or ingestion.

• Sensitivity to topically administered aminoglycosides may occur in some patients.

• 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. Although these effects have not been reported following topical ocular use of tobramycin, 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.

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.

Pregnancy

High systemic doses of tobramycin, well above those encountered with topical ocular use, have been associated with nephrotoxicity and ototoxicity. Tobramycin crosses the placenta into the foetal circulation and amniotic fluid.A study of orally and parenterally administered aminoglycosides (including tobramycin) to pregnant women demonstrated no detectable risk to the foetus. Systemic exposure following ocular administration is expected to be low. However, TOBRAVISC eye drops should be used during pregnancy only if the potential benefit outweighs the potential risk to the foetus. See section 5.3 concerning studies in pregnant animals.

Breast-feeding mothers

In systemic treatment, tobramycin passes over to human milk in such amounts that there is a risk of affecting the child. When instilled topically, systemic exposure is low, the risk is judged to be low when using TOBRAVISC eye drops. The benefits of treating the mother must be weighed up against the possible risk to the infant.

As with any eye drop, temporary blurred vision or other visual disturbacnces may effect 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.

The most frequent adverse reactions related to TOBRAVISC are symptoms of localized ocular toxicity and hypersensitivity including eyelid pruritus and oedema, ocular hyperaemia, eye pruritus, and increased lacrimation.

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:

Description of selected adverse events

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

Due to the characteristics of this preparation, no toxic effects are to be expected with the ophthalmic use of the product, nor 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.

Pharmacotherapeutic Group: ophthalmologicals; anti-infectives

ATC code: S01A A12

Mode of Action

The preparation contains tobramycin, a rapidily 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 adenylylating, 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:

•Enterobacteriaceae S 2 mg/l, R> 4 mg/l

•Pseudomonas spp. S 4 mg/l, R> 4 mg/l

•Acinetobacter spp. S 4 mg/l, R> 4 mg/l

•Staphylococcus spp. S 1 mg/l, R> 1 mg/l

• Not species-related S 2 mg/l, R> 4 mg/l

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.

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

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.

Systemic administration of high doses of tobramycin to pregnant rodents (30-100 mg/kg/day) during organogenesis was reported to result in renal toxicity and otoxicity in foetuses. Other studies performed in rats and rabbits with tobramycin at doses up to 100 mg/kg/day parenterally (> 400-times the maximum clinical dose) revealed no evidence of impaired fertility or harm to the foetus.

Xanthan gum

Benzododecinium bromide (BDAB)

Mannitol

Trometamol

Boric acid

Polysorbate 80

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

Purified water

Not applicable.

2 years.

Discard four weeks after first opening.

No special precautions for storage.

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

No special requirements.

Alcon Laboratories (UK) Ltd

Pentagon Park

Boundary Way

Hemel Hempstead

HP2 7UD

United Kingdom

PL 00649/0172

14^th July 2005

22/10/2009