Maxitrol^® (Drops) Instructions for Use

Marketing Authorization Holder

Novartis Pharma AG (Switzerland)

Manufactured By

Alcon-Couvreur N.V., S.A. (Belgium)

Contact Information

NOVARTIS PHARMA LLC (Russia)

ATC Code

S01CA01 (Dexamethasone and antimicrobial drugs)

Active Substances

Dexamethasone (Rec.INN registered by WHO)

Neomycin (Rec.INN registered by WHO)

Polymyxin B (Rec.INN registered by WHO)

Dosage Form

Maxitrol®

Eye drops 1 mg+3500 IU+6000 IU/1 ml: dropper bottle 5 ml

Dosage Form, Packaging, and Composition

Eye drops as an opaque suspension from white to light yellow in color, without agglomerates.

Excipients: benzalkonium chloride – 0.04 mg/ml, sodium chloride, polysorbate 20, hypromellose, hydrochloric acid solution 1M and/or sodium hydroxide solution 1M, purified water.

5 ml – low-density polyethylene dropper bottles (1) – cardboard packs.

The presence of a first-opening control on the cardboard pack is allowed.

Clinical-Pharmacological Group

A drug with antibacterial and anti-inflammatory action for topical application in ophthalmology

Pharmacotherapeutic Group

Dexamethasone, in combination with antimicrobials

Pharmacological Action

Mechanism of action

A combined drug for topical application in ophthalmology.

Neomycin exerts a bactericidal action by disrupting bacterial cell protein synthesis. It is active against Staphylococcus aureus, Corynebacterium diphtheriae, Streptococcus viridans, Escherichia coli, Klebsiella pneumoniae, Proteus vulgaris, Aerobacter aerogenes, Haemophilus influenzae.

The mechanism of action of polymyxin B is mainly due to the blockade of the permeability of the cytoplasmic membrane of bacterial cells. It is active against Pseudomonas aeruginosa, Aerobacter aerogenes, Escherichia coli, Klebsiella pneumoniae, Koch-Weeks bacillus.

Dexamethasone is a glucocorticosteroid. It exerts anti-inflammatory, anti-allergic, and desensitizing action. It has an anti-exudative effect. Dexamethasone effectively suppresses inflammatory processes.

The combination of a glucocorticosteroid with antibiotics allows to reduce the risk of developing an infectious process.

Mechanisms of resistance development

Bacterial resistance to polymyxin B is of chromosomal origin and rarely occurs. Apparently, modification of cytoplasmic membrane phospholipids plays a role in this process.

Resistance to neomycin arises due to several different mechanisms:

1 – alteration of the ribosomal subunit inside the bacterial cell;

2 – prevention of neomycin transport into the cell;

3 – inactivation by an array of adenylating, phosphorylating, and acetylating enzymes. Genetic information for the production of inactivating enzymes can be carried on the bacterial chromosome or plasmid.

Breakpoint values

Each milliliter of Maxitrol^® contains 6000 IU of polymyxin B sulfate and 3500 IU of neomycin sulfate. As indicated below, when determining the breakpoint concentration and the range of in vitro exposure, the activity of the double content of either polymyxin B or neomycin is taken into account.

The breakpoint concentrations indicated here are based on the acquired resistance of specific bacterial species found in eye infections and the ratio in IU of polymyxin B to neomycin in Maxitrol^®: resistance breakpoint concentrations from >5:2.5 to >40:20 depending on the bacterial species.

Susceptibility

The information listed below provides an idea of the approximate probability of susceptibility of microorganisms to polymyxin B or neomycin contained in the drug. The following are types of microorganisms isolated from external eye infections.

The prevalence of acquired resistance for selected species may vary geographically and over time. If necessary, if the local prevalence of resistance is such that the applicability of the combination of polymyxin B or neomycin in Maxitrol^® is at least questionable for some types of infections, a specialist should be consulted.

Susceptible microorganisms

Aerobic Gram-positive microorganisms

Bacillus cereus, Bacillus megaterium, Bacillus pumilus, Bacillus simplex, Corynebacterium accolens, Corynebacterium bovis, Corynebacterium macginleyi, Corynebacterium propinquum, Corynebacterium pseudodiphtheriticum, Staphylococcus aureus (methicillin-sensitive – MSSA), Staphylococcus capitis, Staphylococcus epidermidis (methicillin-sensitive – MSSE), Staphylococcus pasteuri, Staphylococcus warneri, Streptococcus mutans.

Aerobic Gram-negative microorganisms

Haemophilus influenza, Klebsiella pneumoniae, Moraxella catarrhalis, Moraxella lacunata, Pseudomonas aeruginosa, Serratia species.

Microorganisms with intermediate susceptibility

Staphylococcus epidermidis (methicillin-resistant – MRSE), Staphylococcus hominis, Staphylococcus lugdunensis.

Resistant microorganisms

Aerobic Gram-positive microorganisms

Enterococcus faecalis, Staphylococcus aureus (methicillin-resistant – MRSA), Streptococcus mitis, Streptococcus pneumonia.

Anaerobic bacteria

Propionibacterium acnes.

Pharmacokinetics

Absorption

Dexamethasone, like other corticosteroids, can enter the systemic circulation through the skin of the eyelids and conjunctival vessels after topical application in ophthalmology.

Distribution and elimination

Dexamethasone penetrates significantly into the intraocular fluid, which provides a pronounced anti-inflammatory effect when used in the therapy of inflammatory diseases of the anterior segment of the eyeball.

Polymyxin sulfate is not absorbed through intact skin; intact corneal epithelium prevents the drug from penetrating into the corneal stroma. Therapeutic concentrations of polymyxin B in the corneal stroma are achieved when it penetrates through damaged corneal epithelium; optimal penetration into the corneal stroma in case of corneal erosion is achieved by instillation and subconjunctival administration. There are no data on achieving high concentrations of polymyxin B in the vitreous body when the drug is used as instillations.

Neomycin is absorbed through the skin in its inflammatory diseases or violation of the integrity of the skin and is rapidly excreted by the kidneys in active form.

Indications

The drug Maxitrol^® is intended for short-term therapy of diseases of the organ of vision in children, adults, including the elderly, in which the use of corticosteroids is indicated and which require prophylactic administration of antibacterial therapy

• For infections of the eye and its appendages – blepharitis, conjunctivitis, blepharoconjunctivitis, keratitis, iridocyclitis after exclusion of viral and fungal etiology of the disease;
• For the prevention of postoperative infectious complications.

ICD codes

Dosage Regimen

1 or 2 drops up to 6 times/day into each affected eye. More frequent instillations are possible if the clinical situation requires it.

Children

The dosage regimen of the drug in children corresponds to that in adults.

Method of application

For topical ophthalmic use. Shake the bottle before use.

Do not touch the tip of the dropper bottle to the eyelids or any surface to avoid contamination of the dropper bottle and its contents. After removing the cap, if the snap-on rim with tamper evidence is not attached to the neck, it must be removed before using the drug.

After application of Maxitrol^®, nasolacrimal occlusion is recommended or the eye should be closed gently. This may reduce systemic absorption of the drug when applied topically and thereby reduce the likelihood of systemic adverse reactions.

The bottle must be closed after each use.

In case of use with other topical ophthalmic drugs, the interval between their applications should be at least 5 minutes. Eye ointments should be applied last.

Adverse Reactions

Summary of the safety profile

In clinical trials of the fixed combination of dexamethasone, neomycin, and polymyxin B for ophthalmic use, the most frequent adverse reactions (ARs), which were observed in 0.7-0.9% of patients, were eye discomfort, keratitis, and irritation of the eye mucosa.

Tabulated summary of adverse reactions

ARs are listed using the following frequency conventions: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10000 to <1/1000), very rare (<1/10000), frequency not known (cannot be estimated from the available data). Within one frequency category, ARs are presented in order of decreasing severity.

The following ARs were identified during clinical trials and post-registration experience with Maxitrol^®, eye drops.

Description of selected adverse reactions

Due to the content of the steroid component, in diseases causing thinning of the cornea or sclera, there is an increased risk of their perforation, especially in the context of long-term therapy.

Long-term topical use of corticosteroids for the treatment of ophthalmic diseases can lead to increased intraocular pressure with damage to the optic nerve, decreased visual acuity and visual field defects, as well as the development of posterior subcapsular cataract.

Some patients may exhibit sensitivity to topically applied aminoglycosides.

The development of a secondary infection is observed after the use of combined preparations containing corticosteroids or antimicrobial substances (see the “Special Precautions” section).

Other side effects associated with the individual components of Maxitrol^® are listed in the relevant instructions for medical use of the single-component medicinal products.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after registration of a medicinal product in order to ensure continuous monitoring of the benefit-risk ratio of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse drug reactions through the national adverse reaction reporting system of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to the active substances or to any of the excipients included in the drug;
• Superficial forms of keratitis caused by Herpes simplex, in particular dendritic keratitis;
• Vaccinia, varicella and other viral eye diseases;
• Mycobacterial eye infection;
• Acute herpes zoster;
• Fungal eye diseases or previously untreated parasitic eye infections.

Use in Pregnancy and Lactation

Pregnancy

Data on the use of dexamethasone, neomycin or polymyxin B in pregnant women are limited or absent.

Aminoglycoside antibiotics, in particular neomycin, after their intravenous administration to pregnant women, cross the placental barrier. Preclinical and clinical studies have shown that aminoglycosides, in case of their systemic use, have ototoxic and nephrotoxic effects. In the case of using low doses of neomycin contained in this drug, its ototoxic and nephrotoxic effects as a result of exposure in the prenatal period are not expected. In a study in rats in which animals were administered neomycin orally at doses up to 25 mg/kg/day, no signs of toxic effects on the maternal body, as well as fetotoxic or teratogenic effects, were identified.

Long-term or repeated use of glucocorticosteroids during pregnancy has been associated with an increased risk of intrauterine growth retardation. Infants whose mothers received glucocorticosteroids in sufficiently high doses during pregnancy should be closely monitored for signs of adrenal insufficiency (see the “Special Precautions” section). Animal studies have shown toxic effects on reproduction after systemic and ophthalmic use of dexamethasone.

There are no safety data for polymyxin B in pregnant animals.

The use of Maxitrol^® during pregnancy is not recommended.

Breastfeeding period

It is not known whether Dexamethasone, neomycin or polymyxin B for topical ophthalmic use are excreted in breast milk.

After systemic use in women, aminoglycosides pass into breast milk. Data on the ability of dexamethasone and polymyxin B to penetrate into human breast milk are lacking. The detection of dexamethasone, neomycin and polymyxin B in breast milk and their ability to cause clinically significant effects in infants whose mothers received this drug for topical use seem unlikely. However, since systemic corticosteroids and aminoglycosides can pass into breast milk, the risk to breastfed children cannot be excluded.

A decision should be made on the need to interrupt or discontinue the use of the drug, taking into account the benefit of breastfeeding for the child and the benefit of therapy for the mother.

Fertility

There are no data on the effect of neomycin or polymyxin B on male or female fertility.

Clinical data to evaluate the effect of dexamethasone on male or female fertility are limited. In experimental studies in rats primed with chorionic gonadotropin, no adverse effects of dexamethasone on fertility were noted.

Pediatric Use

The dosage regimen of the drug in children corresponds to that in adults.

Special Precautions

Similar to other anti-infective drugs, prolonged use of antibiotics such as neomycin and polymyxin may lead to increased growth of resistant organisms, including fungi. If superinfection develops, the use of the drug should be discontinued and alternative therapy initiated.

Some patients may develop sensitivity to topically applied aminoglycosides, such as neomycin. Cross-hypersensitivity to other aminoglycosides may develop.

Hypersensitivity reactions can be of varying severity and range from local effects to generalized reactions, including erythema, itching, urticaria, rash, anaphylaxis, anaphylactoid reactions, or bullous reactions.

If hypersensitivity develops during the use of Maxitrol^®, treatment should be discontinued.

If inflammation or pain persists for 48 hours or increases, patients are advised to discontinue the use of Maxitrol^® and consult an ophthalmologist.

In patients who received neomycin systemically or topically on open wounds or on damaged skin, serious adverse reactions occurred, including neurotoxicity, ototoxicity, and nephrotoxicity. Nephrotoxic and neurotoxic reactions also developed with systemic use of polymyxin B. Despite the absence of reports of these effects after topical ophthalmic use of this drug, caution is recommended when used concomitantly with systemic therapy with aminoglycosides or polymyxin B.

Long-term use of ophthalmic corticosteroids can lead to increased intraocular pressure and/or glaucoma with damage to the optic nerve, decreased visual acuity and visual field defects, and the formation of posterior subcapsular cataract. Therefore, in patients using ophthalmic glucocorticosteroid-containing drugs for a long time, intraocular pressure should be measured regularly. This is especially important in pediatric practice, as the risk of increased intraocular pressure due to corticosteroid use is higher in children and may occur earlier than in adults.

The risk of increased intraocular pressure and/or cataract formation due to corticosteroid use is higher in predisposed patients (e.g., with diabetes).

In predisposed patients, including children and patients receiving treatment with CYP3A4 isoenzyme inhibitors (including ritonavir and cobicistat), after intensive therapy or continuous long-term therapy, Cushing’s syndrome and/or adrenal suppression may occur due to systemic absorption of dexamethasone for ophthalmic use (see the “Drug Interactions” section). In such cases, the drug should be discontinued not immediately, but gradually.

Regular biomicroscopy of the anterior segment of the eyeball should be performed to monitor the course of deep herpetic keratitis due to the possibility of worsening their course against the background of drug use.

It is known that in diseases that cause thinning of the cornea or sclera, perforations may occur as a result of the use of topical corticosteroids.

Corticosteroids may reduce resistance to bacterial, fungal, viral infections or parasitic infestations and promote their development, as well as mask the clinical signs of infection.

The appearance of non-healing ulcers on the patient’s cornea may indicate the development of a fungal infection. If a fungal infection develops, corticosteroid therapy should be discontinued.

Topically applied corticosteroids may slow the healing process of corneal damage. It is known that topical NSAIDs also slow down or delay healing. The concomitant use of topical NSAIDs and topical steroids may increase the likelihood of healing impairments (see the “Drug Interactions” section).

Wearing contact lenses is not recommended during the treatment of infectious or inflammatory eye diseases.

Excipients

The preparation contains benzalkonium chloride, which may cause eye irritation and stain soft contact lenses. Contact of the preparation with soft contact lenses should be avoided. However, if the doctor believes that the patient can wear contact lenses, then the patient should be instructed to remove the contact lenses before using the preparation and reinsert them no earlier than 15 minutes after instillation.

The bottle must be closed after each use.

Shake the bottle before use.

Influence on the ability to drive vehicles and mechanisms

Temporary blurring of vision or other visual impairments may affect the ability to drive a car or operate machinery. If the patient experiences temporary blurring of vision after using the preparation, they should wait until their vision clears before driving a car or operating machinery.

Overdose

There are no data on cases of overdose.

Symptoms that are possible include punctate keratitis, lacrimation, itching of the eyelids, hyperemia of the eyelids and conjunctiva.

When using the preparation Maxitrol^®, eye drops, toxic effects are unlikely both with topical use in recommended doses and with accidental ingestion of the contents of the bottle.

Treatment if an excessive amount of the preparation gets into the eyes, rinse the eyes with warm water.

Drug Interactions

Concomitant use of topical steroids and topical NSAIDs may increase the likelihood of corneal healing impairments.

Inhibitors of the CYP3A4 isoenzyme, including ritonavir and cobicistat, can increase the level of systemic exposure, leading to an increased risk of adrenal function suppression/Cushing’s syndrome (see the “Special Instructions” section). The combination of these drugs should be avoided, except in cases where the beneficial effect outweighs the increased risk of systemic side effects of corticosteroids, but in this case, the patient should be carefully monitored for the occurrence of systemic effects of corticosteroids.

Concomitant and/or sequential use of aminoglycosides (neomycin) with other systemic, oral and topical preparations that have neurotoxicity, ototoxicity and nephrotoxicity should be avoided due to the possibility of potentiation of these effects.

Storage Conditions

The preparation should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 2 years.

After opening the bottle, the preparation should be used within 28 days.

Dispensing Status

The preparation is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.