TOBRADEX 3 mg/ml/1 mg/ml Eye Drops, Suspension

Each ml contains: Tobramycin 3 mgDexamethasone 1 mg

For excipients, see section 6.1.

Eye Drops, Suspension

White to off-white suspension

TOBRADEX is indicated for reduction of intraocular inflammation and ocular surface bacterial contamination after cataract surgery.

When prescribing TOBRADEX, consideration should be given to official guidance on the appropriate use of antibacterial agents.

Adults:

One drop instilled into the conjunctival sac(s) every 4 to 6 hours while the patient is awake. During the initial 24 to 48 hours, the dosage may be increased to one drop every two hours while the patient is awake. Dosing should continue for 14 days not to exceed a maximum of 24 days. Frequency should be decreased gradually as warranted by improvement in clinical signs. Care should be taken not to discontinue therapy prematurely.

Use in the Elderly:

Clinical studies have indicated dosage modifications are not required for use in the elderly.

Children and Adolescents:

TOBRADEX is not recommended for use in children and adolescents less than 18 years of age.

Shake the bottle well before use. To prevent contamination of the dropper tip and suspension, care should 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 ophthalmic medicinal products, an interval of 10 minutes should be allowed between successive applications.

Epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, varicella and other viral disease of the cornea and conjunctiva. Mycobacterial infections of the eye caused by, but not limited to, acidfast bacilli such as Mycobacterium tuberculosis, Mycobacterium leprae, or Mycobacterium avium. Fungal diseases of ocular structures. Untreated purulent infection of the eye. Hypersensitivity to tobramycin or dexamethasone or to any of the excipients.

TOBRADEX is for topical use only and not for injection or oral use. Prolonged use (i.e., longer than the maximum duration used in clinical trials [24 days]) may result in ocular hypertension/glaucoma with resultant damage to the optic nerve and defects in visual acuity and visual fields. Prolonged use of steroids may also result in posterior subcapsular cataract formation. Prolonged use may also result in secondary ocular infections due to suppression of host response. Acute purulent infections of the eye may be masked or exacerbated by the presence of corticosteroids . In those diseases causing thinning of the cornea or sclera, perforation has been known to occur with topical steroids. It is advisable that the intraocular pressure be checked frequently.

Sensitivity to topically applied aminoglycosides may occur in some patients. If sensitivity does occur, discontinue use.

Benzalkonium chloride, used as a preservative in this product, has been reported to cause punctate keratopathy and/or toxic ulcerative keratopathy. Benzalkonium chloride may cause eye irritation and discolour soft contact lenses. Contact lenses should be removed before instillation and not reinserted for at least 15 minutes.

No specific interactions studies were performed with TOBRADEX.

Pregnancy:

There are no adequate data from the use of TOBRADEX in pregnant women. Animal studies with subcutaneous administration of tobramycin have not revealed any teratogenic effects. High systemic doses of aminoglycoside antibiotics have been associated with ototoxicity. However, after ocular, topical administration, systemic levels are expected to be very low and tobramycin is not expected to cause direct or indirect harmful effects on reproduction. Topical administration of corticosteroids to pregnant animals can cause abnormalities in foetal development, including cleft palate. The clinical relevance is not known. Further, animal and clinical data indicate that administration of pharmacological doses of glucocorticoids during pregnancy may increase the risk for intrauterine growth retardation, adult cardiovascular and/or metabolic disease and/or impaired neurobehavioral development. Treatment during pregnancy, and especially during the first three months, should only take place after a careful benefit-risk assessment. Therefore, women should inform their physician if pregnancy occurs. So far, use in humans has not generated any suspicion of embryotoxic effects. However, during long-term treatment growth disorders in the unborn child cannot be ruled out. Treatment towards the end of pregnancy may inhibit the body's own production of glucocorticoids necessitating treatment after birth. Therefore, during pregnancy, TOBRADEX should only be used when the potential benefit justifies the potential risks.

Lactation:

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 product detectable quantities in human milk. TOBRADEX should not be used during breast-feeding unless the potential benefit outweighs the potential risk

No studies on the effects on the ability to drive and use machines have been performed. As with any eye drop, temporarily blurred vision or other visual disturbances may effect the ability to drive or use machines. If blurred vision occurs, the patient must wait until the vision is clear before driving or using machines.

In clinical studies involving over 600 patients, TOBRADEX was administered up to six times daily. No serious ophthalmic or systemic adverse reactions related to TOBRADEX or components of the combination were reported in clinical studies. The most frequently reported treatment-related undesirable effect with TOBRADEX was eye irritation (burning upon instillation) (0.8%).

The following adverse reactions have been reported with TOBRADEX or one of its components either during clinical trials or during postmarketing experience:

Common:>1/100 to < 1/10; Uncommon:> 1/1000 to 1/100

Nervous system disorders:

TOBRADEX ophthalmic suspension:

Uncommon: headache*

Dexamethasone ophthalmic suspension:

Common: headache*

Eye disorders:

TOBRADEX ophthalmic suspension:

Uncommon: ocular irritation,* eye pain,* eye pruritus,* ocular hyperaemia,* ocular discomfort,* ocular hypertension,* eye allergy, keratitis,* foreign body sensation in eyes, conjunctival oedema, blurred vision,* dry eye

Tobramycin ophthalmic solution:

Common: ocular hyperaemia,* eye pain*

Uncommon: eye pruritus,* ocular discomfort,* eye allergy, eyelid oedema,* conjunctivitis,* glare, increased lacrimation,* keratitis*

Dexamethasone ophthalmic suspension:

Common: eye irritation,* ocular hyperaemia,* erythema of eyelid, abnormal sensation in eye*

Respiratory, thoracic, and mediastinal disorders:

TOBRADEX ophthalmic suspension:

Uncommon: rhinorrhoea,* laryngospasm

Dexamethasone ophthalmic suspension:

Common: postnasal drip

Investigations:

TOBRADEX ophthalmic suspension:

Uncommon: increased intraocular pressure*

* These adverse reactions were also observed with TOBRADEX during postmarketing.

A review of all spontaneous postmarketing adverse events since the launch of TOBRADEX has indicated no change in the safety profile based upon the evaluation of all ocular, systemic and pharmacological class effects.

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

Pharmacotherapeutic group: Anti-inflammatory agents and anti-infectives in combination, corticosteroids and anti-infectives in combination

ATC code: S01C A01

Dexamethasone:

The efficacy of corticosteroids for the treatment of inflammatory conditions of the eye is well established. Corticosteroids achieve their anti-inflammatory effects through suppression of vascular endothelial cell adhesion molecules, cyclooxygenase I or II, and cytokine expression. This action culminates in a reduced expression of pro-inflammatory mediators and the suppression of adhesion of circulating leukocytes to the vascular endothelium, thereby preventing their migration into inflamed ocular tissue. Dexamethasone has marked anti-inflammatory activity with reduced mineralocorticoid activity compared with some other steroids, and is one of the most potent anti-inflammatory agents.

Tobramycin:

Tobramycin is a potent, broad-spectrum, rapidly bactericidal aminoglycoside antibiotic. It exerts its primary effect on bacterial cells by inhibiting polypeptide assembly and synthesis on the ribosome. Tobramycin in this combination provides antibacterial protection against susceptible bacteria.

The following MIC breakpoints, separating susceptible from intermediate susceptible organisms, and intermediate susceptible from resistant organisms, are suggested: S ( < 4 μg/ml, R (> 8 μg/ml). The prevalence of 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 the agent in at least some types of infections is questionable. The following information gives only an approximate guidance on probabilities whether bacteria will be susceptible to tobramycin in TOBRADEX.

The breakpoint definitions classifying isolates as susceptible or resistant are useful in predicting clinical efficacy of antibiotics that are administered systemically. However, when the antibiotic is administered in very high concentrations topically directly on the site of infection, these breakpoint definitions may not be applicable. Most isolates that would be classified as resistant by systemic breakpoints are indeed successfully treated topically.

In vitro studies have shown tobramycin to be active against most strains of common ocular pathogens and common skin flora bacteria as listed in the Table below:

^a Methicillin-susceptible (S), Methicillin-resistant (R). The beta-lactam (i.e., methicillin; penicillin) resistance phenotype is unrelated to the aminoglycoside resistance phenotype and both are unrelated to the virulence phenotypes. Some methicillin-resistant (R) S. aureus strains (MRSA) are susceptible to tobramycin (MIC: S <4); conversely some strains of methicillin–susceptible (S) S. aureus (MSSA) are resistant to tobramycin (MIC: S >8)

The frequency of methicillin resistance (R) may be up to 50 % of all staphylococci in some European countries

Other information

Cross-resistance between aminoglycosides (e.g., gentamicin and tobramycin) is due to the specificity of the enzyme modifications, Adenyltransferase (ANT) and Acetyltransferase (ACC). However, cross-resistance varies between the aminoglycoside antibiotics due to the differing specificity of the various modifying enzymes. The most common mechanism of acquired resistance to aminoglycosides is antibiotic inactivation by plasmid and transposon-encoded modifying enzymes.

Tobramycin:

Animal studies have shown that tobramycin is absorbed into the cornea following ocular administration. Following systemic administration to patients with normal renal function, a plasma half-life of approximately 2 hours has been observed. Tobramycin is eliminated almost exclusively by glomerular filtration with little if any biotransformation. Plasma concentrations of tobramycin following the 2-day topical ocular regimen of TOBRADEX were below the limit of quantification in most subjects or low ( 0.25 microgram/ml).

Dexamethasone:

Following ocular administration, dexamethasone is absorbed into the eye with maximum concentrations in the cornea and aqueous humour attained within 1-2 hours. The plasma half-life of dexamethasone is approximately 3 hours. Dexamethasone is eliminated extensively as metabolites. Systemic exposure to dexamethasone is low following topical ocular administration of TOBRADEX. Peak dexamethasone plasma levels after the last topical dose ranged from 220 to 888 pg/ml (mean 555 ± 217 pg/ml) after administration of one drop of TOBRADEX to each eye four times per day for two consecutive days.

The systemic toxicity profile of the individual actives is well established. Preclinical effects of tobramycin and dexamethasone were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to human use.

Disodium edetate

Hydroxyethylcellulose

Benzalkonium chloride

Purified water

Sodium chloride

Sodium sulphate anhydrous

Sulphuric acid for pH adjustment and / or

Sodium hydroxide for pH adjustment

Tyloxapol

Not applicable

3 years

After the first opening of the container, the sterile ophthalmic suspension should not be used longer than four weeks.

No special precautions for storage.

5 ml dropper container (LDPE) and screw cap (polypropylene).

Pack size: 1x5 ml

No special requirements

Alcon Laboratories UK, Ltd.

Pentagon Park

Boundary Way

Hemel Hempstead

Herts HP2 7UD

England

PL0649/0119

31 January 2001

July 2005