TOBRADEX Eye Drops

Each ml contains the following active ingredients:

Tobramycin 0.3% w/v (3 mg)

Dexamethasone 0.1% w/v (1 mg)

For excipients, see section 6.1.

Eye Drops, Suspension

TOBRADEX Eye Drops are indicated for reduction of inflammation and prophylaxis of infection following cataract surgery.

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, for 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

Safety and effectiveness in children have not been established.

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.

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, acid-fast bacilli such as Mycobacterium tuberculosis, Mycobacterium leprae, or Mycobacterium avium. Fungal diseases of ocular structures. Untreated purulent infection of the eye. Hypersensitivity to any component of the medication.

TOBRADEX Eye Drops are 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 corticosteroid medication. 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.

No specific interaction studies were performed with TOBRADEX Eye Drops.

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

Pregnancy

Safety for use during pregnancy and lactation in humans has not been established. No adequate and well-controlled studies in pregnant women have been conducted. Subcutaneous administration of tobramycin to pregnant animals has not revealed any teratogenic effects. There may be a risk of fetal ototoxicity if aminoglycoside antibiotics are administered during human pregnancy. Topical administration of corticosteroids to pregnant animals can cause abnormalities of fetal development including cleft palate and intra-uterine growth retardation. Therefore, a very small risk exists for such effects in human pregnancy. TOBRADEX Eye Drops should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Lactation

Studies have not been conducted to determine if these drugs are secreted in human milk. Because many drugs are secreted in human milk, a decision should be taken to discontinue nursing while using TOBRADEX Eye Drops.

As with any ocular medication, if transient blurred vision occurs at instillation, the patient should wait until the vision clears before driving or using machinery.

Adverse reactions have occurred with steroid/antiinfective combination drugs, which can be attributed to the steroid component, the anti-infective component, or the combination. Exact incidence figures are not available. The most frequent adverse reactions to topical ocular tobramycin are hypersensitivity and localised ocular toxicity, including lid itching and swelling, and conjunctival erythema. These reactions occur in less than 4% of patients. Similar reactions may occur with the topical use of other aminoglycoside antibiotics. If topical ocular tobramycin is administered concomitantly with systemic aminoglycoside antibiotics, care should be taken to monitor the total serum concentration. The reactions due to the steroid component are: elevation of intraocular pressure (IOP), with possible development of glaucoma, and infrequent optic nerve damage; posterior subcapsular cataract formation; and delayed wound healing.

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

Pharmacotherapeutic Class:

Anti-inflammatory Anti-infective 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 elaboration of pro-inflammatory mediators and the suppression of adhesion of circulation leukocytes to the vascular endothelium, thereby preventing their aggression 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

Endophthalmitis is most frequently caused by Gram-positive bacteria (80-90%) including staphylococci, Bacillus species and streptococci, while Gram-negative organisms account for 10 to 20 percent of cases. The antibiotic component (tobramycin) in the combination is included to provide antibacterial protection against susceptible bacteria. In vitro studies have shown tobramycin to be a broad spectrum antibiotic active against most common ocular pathogens, including methicillin-susceptible and methicillin-resistant staphylococci, some streptococci and most all Gram-negative species. Recent studies with tobramycin have shown the compound to be active (MIC < 8ug/ml) against recently isolated Gram-positive ocular isolates (68%), and against Gram-negative bacteria (98%) as shown in the following list of organisms with potential to cause endophthalmitis.

Gram-Positive:

Methicillin-susceptible Staphylococcus aureus

Methicillin-resistant S. aureus

Methicillin-susceptible S. epidermidis

Methicillin-resistant S. epidermidis

Other coagulase-negative Staphylococcus species

Streptococcus pneumoniae-Penicillin susceptible

Streptococcus species

Gram-Negative:

Acinetobacter spp.

Citrobacter spp.

Enterobacter spp.

Escherichia coli

Haemophilus influenzae (beta lactamase-negative and -positive)

Klebsiella pneumoniae

Moraxella spp.

Neisseria meningitidis

Proteus mirabilis

Pseudomonas aeruginosa

Serratia marcescens

Tobramycin

Animal studies have shown that tobramycin is absorbed into the cornea following ocular administration, but systemic absorption was not measured. 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.

Dexamethasone

Following ocular administration, dexamethasone is absorbed into the eye with maximum concentrations in the cornea and aqueous humour attained within 1-2 hours. Plasma concentrations in man following ocular administration of TOBRADEX Eye Drops have not been measured. The plasma half-life of dexamethasone is approximately 3 hours. Dexamethasone is eliminated extensively as metabolites.

The systemic toxicity profile of the individual actives is well established. Repeated dose toxicity studies with TOBRADEX Eye Drops revealed systemic corticosteroid effects in rabbits, but at doses sufficiently in excess of human exposure to be of little clinical relevance. Mutagenicity and carcinogenicity studies have not been conducted with TOBRADEX Eye Drops

▪ Disodium edetate

▪ Hydroxyethylcellulose

▪ Preservative: Benzalkonium chloride (0.01%)

▪ Purified water

▪ Sodium chloride

▪ Sodium sulphate

▪ Sulphuric acid and / or sodium hydroxide

▪ Tyloxapol

None known.

36 months.

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

Do not store above 25°C.

Do not refrigerate or freeze.

TOBRADEX Eye Drops are packaged in a 5 ml opaque low-density polyethylene (LDPE), DROP-TAINER with a LDPE dispensing plug and a 15 mm white tamper evident polypropylene closure.

Not applicable.

Alcon Laboratories UK, Ltd.

Pentagon Park

Boundary Way

Hemel Hempstead

Herts HP2 7UD

England

PL0649/0119

31^st January 2001

February 2001

Feb01