SUMMARY OF PRODUCT CHARACTERISTICS

1.    NAME OF THE MEDICINAL PRODUCT

MAXITROL ointment

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

1 gram ointment contains 1 mg dexamethasone , 6000 IU polymyxin B sulphate, and 3500 IU neomycin sulphate (as base).

For a full list of excipients, see section 6.1.

3.    PHARMACEUTICAL FORM

Eye ointment

White to very pale yellow homogeneous translucent ointment

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

MAXITROL eye ointment 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.

4.2    Posology and method    of administration

Children and Adults (including the Elderly)

Apply a small amount into the conjunctival sac(s) up to three to four times daily or, may be used adjunctively with drops at bedtime.

4.3    Contraindications

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

•    Herpes simplex keratitis.

•    Vaccinia, varicella, and other viral infection of cornea or conjunctiva.

•    Fungal diseases of ocular structures.

•    Mycobacterial ocular infections.

4.4    Special warnings and    precautions for use

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

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

•    Sensitivity to topically applied aminoglycosides may occur in some patients. Crosssensitivity to other aminoglycosides may also occur. If signs of serious reactions or hypersensitivity occur, discontinue use of MAXITROL eye ointment.

•    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 corticosteroids 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. This is especially important in paediatric patients, as the risk of corticosteroid induced ocular hypertension may be greater in children and may occur earlier than in adults.

• The risk of corticosteroid-induced raised intraocular pressure and/or cataract formation is increased in predisposed patients (e.g. diabetes).

•    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 non-susceptible bacterial, viral, or fungal infections and mask the clinical signs of infection, or may suppress hypersensitivity reactions to substances in the product. Fungal infection should be suspected in patients with persistent corneal ulceration who have been or are receiving these drugs and corticosteroid therapy should be discontinued if fungal infection occurs.

•    To avoid the risk of enhancement of herpetic corneal disease, frequent slip lamp examination is essential.

•    Topical ophthalmic corticosteroids may slow corneal wound healing. Topical NSAIDs

are also known to slow or delay healing. Concomitant use of topical NSAIDs and topical

steroids may increase the potential for healing problems. (See section 4.5).

•    Contact lens wear is discouraged during treatment of an ocular infection. Therefore patients should be advised not to wear contact lenses during treatment with MAXITROL eye ointment.

•    This product contains methylparahydroxybenzoate and propylparahydroxybenzoate which may cause allergic reactions (possibly delayed).

•    This product also contains lanolin which may cause local skin reactions (e.g. contact dermatitis).

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

Concomitant use of topical steroids and topical NSAIDs may increase the potential for corneal healing problems.

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.

4.6 Fertility, pregnancy and lactation

Fertility

There are no data available on the use of this medicine affecting male or female fertility.

Pregnancy

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

MAXITROL eye ointment 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 on whether to discontinue/abstain from breast-feeding or to discontinue

therapy with MAXITROL eye ointment taking into account the benefit of breastfeeding for the child and the benefit of the product to the woman.

4.7 Effects on Ability to Drive and Use Machines

MAXITROL eye ointment 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.

4.8 Undesirable effects

In clinical trials with MAXITROL eye drops and MAXITROL eye ointment the most common adverse reactions were ocular discomfort, keratitis and eye irritation, occurring in 0.7% to 0.9% of patients.

Tabulated summary of adverse reactions

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 <1/1000), very rare (<1/10,000) or not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are

presented in decreasing order of seriousness. clinical trials and post-marketing experience.	The adverse reactions were obtained from
System Organ Classification	MedDRA Preferred Term (v.13.1)
Immune system disorders	Uncommon: hypersensitivity (systemic or ocular)
Nervous system disorders	Not known: headache
Eye disorders	Uncommon: keratitis, intraocular pressure increased, vision-blurred, photophobia, mydriasis, eyelid ptosis, eye pain, eye swelling, eye pruritus, ocular discomfort, foreign body sensation in eyes, eye irritation, ocular hyperaemia, increased lacrimation
	Not known: corneal thinning

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 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 Special warnings and precautions for use).

Sensitivity to topically administered aminoglycosides may occur in some patients (See Section Special warnings and precautions for use). Systemic side effects may occur with extensive 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 national reporting system:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov .uk/yellowcard

4.9 Overdose

No case of overdose has been reported.

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

Due to the characteristics of this preparation, intended for topical use, no toxic effects are expected when administered to the eye neither at the recommended dose nor in the event of accidental ingestion of the contents of a bottle.

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

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: ophthalmologicals; anti-infectives ATC code: S01CA01

Mechanism of Action

MAXITROL eye ointment has a dual effect: suppression of inflammation symptoms by the corticosteroidal component dexamethasone, and an anti-infective 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 ointment 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 ointment:

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 ointment. 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 ointment in at least some types of infections is questionable.

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

5.2. Pharmacokinetic Properties

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.

5.3 Preclinical Safety Data

Mutagenicity and Carcinogenicity

Genotoxicity studies performed with neomycin and polymyxin B, with and without metabolic activation, were negative in bacterial (Ames test) or mammalian cells (chromosomal aberration assay in CHO cells). Dexamethasone was clastogenic in vivo in the mouse micronucleus assay at doses in excess of those obtained following topical application. Conventional long term carcinogenicity studies with MAXITROL or its active constituents have not been performed.

Teratogenicity

Pregnant rats treated daily with high doses of neomycin produced offspring that exhibited significant ototoxicity. The teratogenic dose is far greater (> 10,000fold) than the clinical daily exposure from MAXITROL. Dexamethasone has been found to be teratogenic in animal models. Dexamethasone induced abnormalities of foetal development including cleft palate, intra-uterine growth retardation and affects on brain growth and development.

Local Tolerance and Systemic Effects

Systemic exposure to dexamethasone is associated with its pharmacological effects as a potent glucocorticoid. Prolonged exposure to the steroid can result in glucocorticoid imbalance. Topical ocular safety studies with dexamethasone in rabbits have shown systemic effects after 1 month of treatment. In rabbits, MAXITROL was shown to have minimal irritation potential after administration to either control or irritated eyes.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Methylparaben

Propylparaben Liquid lanolin Petrolatum

Incompatibilities

None known.

6.3    Shelf Life

48 months

Discard 28 days after first opening

6.4.    Special Precautions for Storage

Do not store above 25 °C. Keep away from direct sunlight. Do not refrigerate. Keep the container tightly closed.

6.5.    Nature and Content of Container

3.5    g metal tube with nozzle and screw cap.

6.6    Special precautions for disposal and other handling

Do not touch the top of the tube to any surface as this may contaminate the contents.

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

7    MARKETING AUTHORISATION HOLDER

Alcon Laboratories (UK) Ltd Frimley Business Park,

Frimley, Camberley,

Surrey, GU16 7SR United Kingdom.

8.    MARKETING AUTHORISATION NUMBER

PL 00649/5916R

9.    DATE OF FIRST AUTHORISATION / RENEWAL OF AUTHORISATION

18 January 1991

10 DATE OF REVISION OF THE TEXT

21/07/2015