Alcon Laboratories (U.K) Limited

MAXITROL 0.1%w/v, 6000 IU/ml, 3500 IU/ml eye drops, suspension

1 ml suspension contains 1 mg dexamethasone, 6000 IU polymyxin B sulphate, 3500 IU neomycin sulphate (as base)

Excipients: 1 ml suspension contains 0.04 mg benzalkonium chloride

For a full list of excipients see Section 6.1.

Eye drops, suspension

White to pale yellow opaque suspension

MAXITROL eye drops, suspension is indicated for the short-term treatment of steroid responsive conditions of the eye when prophylactic antibiotic treatment is also required, after excluding the presence of fungal and viral disease.

Children and Adults (including the Elderly)

Apply one or two drops to each affected eye up to six times daily or, more frequently if required.

• Hypersensitivity to the active substances or to any of the excipients.

• Epithelial herpes simplex keratitis.

• Vaccinia, varicella, or other viral infection of cornea and conjunctiva (except herpes zoster keratitis).

• Fungal diseases of ocular structures.

• Mycobacterial ocular infections.

• For ocular use only. Not for injection or ingestion.

• As with all antibacterial preparation prolonged use may lead to overgrowth of non-susceptible bacterial strains or fungi. If superinfection occurs, appropriate therapy should be initiated.

• Sensitivity to topically applied aminoglycosides may occur in some patients. Cross-sensitivity to other aminoglycosides may also occur. If signs of serious reactions or hypersensitivity occur, discontinue the use of this product.

• Patients using ophthalmic preparations containing neomycin sulphate should be advised to consult a physician if ocular pain, redness, swelling, or irritation worsens or persists.

• Serious adverse reactions including neurotoxicity, ototoxicity and nephrotoxicity have occurred in patients receiving systemic neomycin or when applied topically to open wounds or damaged skin. Nephrotoxic and neurotoxic reactions have also occurred with systemic polymyxin B. Although these effects have not been reported following topical ocular use of this product, caution is advised when used concomitantly with systemic aminoglycoside or polymyxin B therapy.

• Prolonged use of ophthalmic steroids may result in ocular hypertension and/or glaucoma, with damage to the optic nerve, reduced visual acuity and visual field defects, and posterior subcapsular cataract formation. In patients receiving prolonged ophthalmic corticosteroid therapy, intraocular pressure should be checked routinely and frequently.

• In those diseases causing thinning of the cornea or sclera, perforations have been known to occur with the use of topical corticosteroids.

• Corticosteroids may reduce resistance to and aid in the establishment of bacterial, viral, or fungal infections and mask the clinical signs of infection, preventing recognition of ineffectiveness of the antibiotic, or may suppress hypersensitivity reactions to MAXITROL eye drops, suspension. Fungal infection should be suspected in patients with persistent corneal ulceration who have been or are receiving these drugs; corticosteroid therapy should be discontinued if fungal infection occurs.

• 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 MAXITROL eye drops, suspension.

• MAXITROL eye drops, suspension contains benzalkonium chloride which may cause eye irritation and is known to discolour soft contact lenses. Patients must be instructed to remove contact lenses prior to application of MAXITROL eye drops, suspension and wait 15 minutes after instillation of the dose before reinsertion.

No interaction studies have been performed.

Concomitant and/or sequential use of an aminoglycoside (neomycin) and other systemic, oral, or topical drugs that have neurotoxic, ototoxic, or nephrotoxic effects may result in additive toxicity and should be avoided, whenever possible.

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

Pregnancy

There are no or limited amount of data from the use of MAXITROL eye drops, suspension in pregnant women. Studies in animals with some active components of MAXITROL eye drops, suspension have shown reproductive toxicity (see section 5.3).

MAXITROL eye drops, suspension is not recommended during pregnancy.

Lactation

It is unknown whether topical ophthalmic dexamethasone, neomycin or polymyxin B are excreted in human milk. Because systemic corticosteroids and aminoglycosides may be distributed into milk, a risk to the suckling child cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from MAXITROL eye drops, suspension therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

MAXITROL eye drops, suspension has no or negligible influence on the ability to drive and use machines. As with any other eye drop, temporarily blurred vision or other visual disturbances may affect the ability to drive or use machines. If transient blurred vision occurs upon instillation, the patient must wait until the vision clears before driving or using machinery.

Tabulated summary of adverse reactions

The following adverse effects 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 <1/1000), very rare (<1/10,000) or not known (cannot be estimated from the available data). Within each frequency grouping, undesirable effects are presented in decreasing order of seriousness. The adverse reactions were obtained from clinical trials and postmarketing spontaneous reports.

Description of selected adverse event

Due to the steroid component, in diseases causing thinning of the cornea or sclera there is a higher risk for perforation especially after long treatments (See Section 4.4 Special warnings and precautions for use).

Topical ophthalmic steroid use may result in increased intraocular pressure with damage to the optic nerve, reduced visual acuity and visual field defects. Also it may lead to posterior subcapsular cataract formation (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).

Systemic side effects may occur with extensive use.

No case of overdose has been reported.

Signs and symptoms of an overdosage of MAXITROL eye drops, suspension may be similar to adverse reaction effects seen in some patients (punctuate keratitis, erythema, increased lacrimation, oedema and lid itching).

A topical ophthalmic overdose of MAXITROL eye drops, suspension may be flushed from the eye(s) with lukewarm water.

Pharmacotherapeutic group: ophthalmologicals; anti-infectives

ATC code: S01CA01

Mechanism of Action

MAXITROL eye drops, suspension has a dual effect: suppression of inflammation symptoms by the corticosteroidal component dexamethasone, and an antiinfective effect due to the presence of two antibiotics, polymyxin B and neomycin.

Dexamethasone is a synthetic glucorticoid with potent anti-inflammatory activity. Polymyxin B is a cyclic lipopeptide that penetrates the cell wall of gram-negative bacilli to destabilize the cytoplasmic membrane. It is generally less active against gram-positive bacteria. Neomycin is an aminoglycoside antibiotic that primarily exerts its effect on bacterial cells by inhibiting polypeptide assembly and synthesis on the ribosome.

Mechanism of Resistance

Resistance of bacteria to polymyxin B is of chromosomal origin and is uncommon. A modification of the phospholipids of the cytoplasmic membrane appears to play a role.

Resistance to neomycin occurs by several different mechanisms including (1) alterations of the ribosomal subunit within the bacterial cell; (2) interference with the transport of neomycin into the cell, and (3) inactivation 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.

Breakpoints

Each gram of MAXITROL eye drops, suspension contains 6000 IU polymyxin B sulphate and 3500 IU neomycin sulphate. The breakpoints and the in vitro spectrum as mentioned below are based on the dual activity of either polymyxin B or neomycin. The breakpoints listed here are based upon acquired resistance for specific species found in ocular infections and the ratio in International Units of polymyxin B to neomycin in MAXITROL eye drops, suspension:

Resistance breakpoints:>5:2.5 to>40:20 depending upon the bacterial species

Susceptibility

The information listed below provides guidance on the approximate probabilities on the susceptibility of microorganisms to polymyxin B or neomycin in MAXITROL eye drops, suspension. The presentation below lists bacterial species recovered from external ocular infections of the eye.

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 the combination of polymyxin B or neomycin as in MAXITROL eye drops, suspension in at least some types of infections is questionable.

Dexamethasone is a moderately powerful corticosteroid having good penetration in ocular tissue. Corticosteroids have an antiinflammatory as well as a vasoconstrictive effect. They suppress the inflammatory response and symptoms in various disorders without basically curing these disorders.

Dexamethasone, like other corticosteroids, is absorbed rapidly after oral administration and has a biological half-life of about 190 minutes. Sufficient absorption may occur after topical application to the skin and eye to produce systemic effects. Intraocular penetration of dexamethasone occurs in significant amounts and contributes to the effectiveness of dexamethasone in anterior segment inflammatory disease.

Polymyxin B sulphate is not absorbed from the gastrointestinal tract or through intact skin, although the intact corneal epithelium prevents penetration into the corneal stroma, therapeutic concentrations do enter the stroma after epithelial damage. Good stromal penetration occurs after epithelial abrasion following topical instillation, subconjunctival injection, or corneal bath. No significant polymyxin B penetration into the vitreous is demonstrable after parenteral or local administration of the drug.

Neomycin is poorly absorbed from the gastrointestinal tract and after topical administration an insufficient amount is absorbed to produce systemic effects. Absorption has been reported to occur from wounds and inflamed skin. After absorption neomycin is rapidly excreted by the kidneys in active form.

Mutagenicity and Carcinogenicity

Neomycin

In vitro treatments of human lymphocytes with neomycin [80 μg/mL] have shown an increase in the frequency of chromosomal aberrations. However, neomycin has also shown to be non-mutagenic in the CHO cell chromosomal aberration assay and the Ames assay. Systemically administered neomycin was found to promote colon tumour development in rats. These concentrations are far in excess (1333-fold) to what would be the systemic exposure from topical dermal formulations.

Dexamethasone

Dexamethasone was shown to be negative in the Ames assay but positive in the in vitro chromosomal aberration assay with human peripheral lymphocytes at doses of 10 and 100 μg/mL and the in vivo mouse micronucleus assay at doses of 1-10 mg/kg.

Teratogenicity

Neomycin

Aminoglycoside antibiotics have been found to cause nephrotoxicity and ototoxicity in animal models. However, there have been no animal reproduction toxicity studies conducted with neomycin.

Dexamethasone

Antenatal administration of glucocorticoids to pregnant animals has been linked to cleft palate and altered neurological development that ultimately lead to complex behavioural abnormalities.

Local Tolerance and Systemic Effects

Dexamethasone

The systemic toxicity profile of dexamethasone is well established and systemic exposure may be associated with the effects of glucocorticoid imbalance.

Sodium chloride

Polysorbate 20

Benzalkonium chloride

Hypromellose

Hydrochloric acid/sodium hydroxide (for pH adjustment only)

Purified water.

Not applicable.

Unopened: 2 years.

Discard 4 weeks after first opening.

Do not store above 25°C. Do not refrigerate or freeze. Store in the original package (to protect from light). Keep the container tightly closed.

5 ml DROP-TAINER, natural or white low density poly-ethylene (LDPE) bottles fitted with a natural LDPE dispensing plugs and white polypropylene (PP) closures.

Do not touch the tip of the bottle to any surface as this may contaminate the contents.

Any unused product or waste materials should be disposed of in accordance with local requirements.

Alcon Laboratories (UK) Ltd

Pentagon Park

Boundary Way

Hemel Hempstead

HP2 7UD

U.K.

PA 290/8/1

Date of first authorisation: 1^st April 1988

Date of last renewal: 1^st April 2008

June 2010