For ocular steroid-responsive inflammatory conditions for which a corticosteroid is indicated and where bacterial ocular infection, or a risk of bacterial ocular infection, exists, due to tobramycin-responsive microorganisms resistant to most of the other antibiotics, especially Pseudomonas aeruginosa, in adults and children aged 2 years and older. See section 5.1.

 

Ocular steroids are indicated in inflammatory conditions of the palpebral and bulbar conjunctiva, cornea and anterior segment of the eye where the inherent risk of steroid use in certain infective conjunctivites is accepted to obtain a decrease in oedema and inflammation. They are also indicated in chronic anterior uveitis and corneal injury from chemical agents, radiation, thermal burns, or penetration of foreign bodies (considering the contraindications).

 

Corticosteroids in eye ointment should be prescribed only after ocular examination.

 

Please consider the official recommendations regarding the adequate use of antibiotics.

Eye ointment:

Posology

Apply a small amount (1 to 1.5 cm) into the conjunctival sac up to 3 or 4 times daily, or use adjunctively with the eye drops during the day and the eye ointment at bedtime.

Gently closing the eyelid and nasolacrimal occlusion after instillation is recommended. This may reduce the systemic absorption of medicinal products administered via the ocular route and result in a decrease in systemic side effects.

 

In case of concomitant therapy with other topical ocular medicinal products, an interval of 5 minutes should be allowed between successive applications. Eye ointments should be administered last.(see section 4.5).

 

Paediatric population

TOBRADEX eye ointment may be used in children 2 years of age and older at the same dose as in adults. Currently available data is described in section 5.1. The safety and efficacy in children younger than 2 years of age have not been established, and no data are available.

 

 

Method of administration

For ocular use.

To prevent contamination of the tube tip and ointment, care must be taken not to touch the eyelids, surrounding areas, or other surfaces with the tube tip. Keep the tube tightly closed when not in use.

1.    Tilt your head back.

2.    Place a finger on your cheek just below your eye and gently pull down until a "V" pocket is formed between your eye and your lower eyelid.

3.    Place a small amount (1 to 1.5 cm) of TOBRADEX eye ointment in the "V" pocket. Do not let the tip of the tube touch your eye.

4.    Look downward for a few moments before closing your eye.

• Hypersensitivity to the active substances or to any of the excipients. • Hypersensitivity to aminoglycosides • Herpes simplex keratitis. • Vaccinia, varicella, and other viral infection of cornea or conjunctiva (except herpes zoster keratitis). • Fungal diseases of ocular structures or untreated parasitic eye infections. • Mycobacterial ocular infections. • Infections or injuries limited to the superficial corneal epithelium. • TOBRADEX should not be used following an uncomplicated removal of a foreign body from the cornea.

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

 

·       The initial prescription and renewal thereof should be made only after examination of the patient with the aid of magnification such as slit-lamp biomicroscopy and, if necessary, fluorescein staining.

 

·       Sensitivity to topically administered aminoglycosides may occur in some patients. Severity of hypersensitivity reactions may vary from local effects to generalized reactions such as erythema, itching, urticarial, skin rash, anaphylaxis, anaphylactoid reactions, or bullous reactions. If hypersensitivity develops during use of this medicine, treatment should be discontinued.

 

·       Cross-hypersensitivity to other aminoglycosides can occur, and the possibility that patients who became sensitized to topical tobramycin may also be sensitive to other topical and/or systemic aminoglycosides should be considered.

 

·       Serious adverse reactions including neurotoxicity, ototoxicity and nephrotoxicity have occurred in patients receiving systemic aminoglycoside therapy. Caution is advised when TOBRADEX is used concomitantly with systemic aminoglycoside (See Section 4.8).

 

·       Caution should be exercised when prescribing TOBRADEX to patients with known or suspected neuromuscular disorders such as myasthenia gravis or Parkinson’s disease. Aminoglycosides may aggravate muscle weakness because of their potential effect on neuromuscular function.

 

·       Excessive and/or prolonged use of topical ophthalmic corticosteroids increases the risk of ocular complications and could cause systemic side effects. If the inflammatory condition does not improve within a reasonable period during the course of the therapy, other forms of therapy should be instituted to reduce these risks.

 

·       Topical application of corticosteroids may be accompanied by a decrease in the urinary secretion of cortisol as well as a decrease in plasma cortisol concentration.  Corticosteroids have been associated with hypothalamic-pituitary-adrenal (HPA) axis suppression, Cushing’s Syndrome, and a decreased rate of growth in children, especially with high-dose or long-term treatment.

 

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 ophthalmic corticosteroid therapy for 10 days or longer, intraocular pressure should be checked routinely and frequently, even though it may be difficult in children and uncooperative patients. 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. Patients with a family or personal history of glaucoma have a higher risk of a corticosteroid-induced rise in intraocular pressure. Patients with glaucoma should be monitored weekly.

 

·       Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

 

·       Cushing’s syndrome and/or adrenal suppression associated with systemic absorption of ocular dexamethasone may occur after intensive or long-term continuous therapy in predisposed patients, including children and patients treated with CYP3A4 inhibitors (including ritonavir and cobicistat). In these cases, treatment should be progressively discontinued.

 

·       Prolonged use of corticosteroids may also reduce resistance to and aid in the establishment of bacterial, viral, fungal or parasitic infections and mask the clinical signs of infection, preventing recognition of ineffectiveness of the antibiotic. TOBRADEX should therefore only be used in acute purulent infections of the eye when treatment with a steroid/anti-infective combination product is medically necessary.  Fungal infection should be suspected in patients with persistent corneal ulceration. If fungal infection occurs, corticosteroids therapy should be discontinued.

 

The use of antibiotics such as tobramycin may also result in overgrowth of non-susceptible organisms, including fungi. If superinfection occurs, appropriate therapy should be initiated.

·       Ocular herpes simplex has occurred in patients under systemic or local corticosteroid therapy for other conditions. Using corticosteroid medication in the treatment of herpes simplex other than epithelial herpes simplex keratitis, in which it is contraindicated, requires great caution; periodic slit-lamp microscopy is essential.

 

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

 

·         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).

 

 

·       Treatment should not be discontinued prematurely as a flare-up of the infectious or inflammatory condition may occur with the sudden interruption of a treatment with antibiotics or high doses of corticosteroids, respectively.

 

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

 

 

·       Contact lens wear is not recommended during treatment of an ocular infection or inflammation.

 

 

Paediatric population

It is advisable that the intraocular pressure be checked frequently. This is especially important in paediatric patients receiving dexamethasone-containing products, as the risk of steroid-induced ocular hypertension may be greater in children below 6 years of age and may occur earlier than a steroid response in adults. The frequency and duration of treatment should be carefully considered, and the IOP should be monitored from the outset of treatment, recognizing the risk for earlier and greater steroid-induced IOP increases in the paediatric patients.

 

·         No interaction studies have been performed.

·         Interactions have been reported with systemic administration of the individual components. Concomitant use of topical steroids and topical NSAIDs may increase the potential for corneal healing Nevertheless, systemic absorption of ophthalmic tobramycin and dexamethasone is low and the chance of any interaction is minimal.  

·         When using pupil-dilating eye drops (atropine and other anticholinergic substances), which may cause elevation of intraocular pressure, concomitant use of TOBRADEX may lead to an additional elevation of intraocular pressure.

·         In patients treated with ritonavir or other strong CYP3A4 inhibitors, plasma concentrations of dexamethasone may be increased (See Section 4.4).

·         CYP3A4 inhibitors (including ritonavir and cobicistat): may decrease dexamethasone clearance resulting in increased effects and adrenal suppression/Cushing’s syndrome. The combination should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side-effects, in which case patients should be monitored for systemic corticosteroid effects.

·         If more than one eye preparation is being used, the products must be administered at least 5 minutes apart. Eye ointments should be administered last.

Fertility

Studies have not been conducted to evaluate the effect of tobramycin on human or animal

fertility. There is limited clinical data to evaluate the effect of dexamethasone on male or

female fertility. Dexamethasone was free of adverse effects on fertility in a chorionic

gonadotropin primed rat model.

 

 

Pregnancy

There are no or limited amount of data from the topical ocular use of tobramycin and dexamethasone in pregnant women. Tobramycin does cross the placenta into the fetus after intravenous dosing in pregnant women. Tobramycin is not expected to cause ototoxicity from in utero exposure. Prolonged or repeated corticoid use during pregnancy has been associated with an increased risk of intra-uterine growth retardation. Infants born of mothers who have received substantial doses of corticosteroids during pregnancy should be observed carefully for signs of hypoadrenalism. Studies in animals have shown reproductive toxicity after topical administration of dexamethasone and after systemic administration of dexamethasone and tobramycin (see section 5.3).

TOBRADEX is not recommended during pregnancy.

 

Breastfeeding

Tobramycin is excreted in human milk after systemic administration. No data is available on

the passage of dexamethasone into human breast milk. It is unknown whether tobramycin and

dexamethasone are excreted in human milk following topical ocular administration. It is not

likely that the amount of Tobramycin and Dexamethasone would be detectable in human

milk or be capable of producing clinical effects in the infant following topical use of the

product.

A risk to the suckling child cannot be excluded. A decision must be made whether to

discontinue breast-feeding or to discontinue/abstain from therapy taking into account the

benefit of breast feeding for the child and the benefit of therapy for the woman.

 

TOBRADEX has no or negligible influence on the ability to drive and use machines. However, temporary blurred vision or other visual disturbances may affect the ability to drive or use machines. If blurred vision occurs at application, the patient must wait until the vision clears before driving or using machines.

 

Summary of the safety profile

No serious ophthalmic adverse events related to TOBRADEX were reported in clinical studies. The most frequently reported treatment-related adverse reactions were eye pain, intraocular pressure increased, eye irritation, and eye pruritus occurring in less than 1% 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 <1/1,000), very rare (<1/10,000), or not known (cannot be estimated from the available data). Within each frequency-grouping, adverse reactions are presented in order of decreasing seriousness. The adverse reactions have been observed during clinical trials and post-marketing experience with TOBRADEX.

 

System Organ Classification	Adverse reactions
Immune system disorders	Not known: hypersensitivity, anaphylactic reaction,
Nervous system disorders	Not known: dizziness, headache
Eye disorders	Uncommon: intraocular pressure increased, eye pain, eye pruritus, ocular discomfort, eye irritation Rare: keratitis, eye allergy, vision blurred, dry eye, ocular hyperaemia Not known: eyelid oedema, erythema of eyelid, mydriasis, lacrimation increased , ulcerative keratitis
Gastrointestinal disorders	Rare: dysgeusia Not known: nausea, abdominal discomfort
Skin and subcutaneous tissue disorders	Not known: rash, swelling face, pruritus, erythema multiforme

 

Description of selected adverse reactions

Topical ophthalmic corticosteroid use may result in increased intraocular pressure with damage to the optic nerve, reduced visual acuity and visual field defect, and posterior subcapsular cataract formation (See Section 4.4. Special warnings and precautions for use).

 

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

 

The development of secondary infection has occurred after use of combinations containing steroids and antimicrobials. Fungal infections of the cornea are particularly prone to develop coincidentally with long term applications of steroids. The possibility of fungal invasion must be considered in any persistent corneal ulceration where steroid treatment has been used. Secondary ocular infection following suppression of host responses also occurs. (See Section 4.4 Special warnings and precautions for use).

 

When administered systemically, tobramycin may induce renal, vestibular and auditory nerve toxicity, especially in patients receiving high doses or prolonged treatment. Doses recommended for ocular administration are significantly lower than those used systemically, and these systemic effects are extremely unlikely with TOBRADEX (See Section 4.4 Special warnings and precautions for use).

Sensitivity to topically administered aminoglycosides may occur in some patients (See Section 4.4).

 

Undesirable effects have occurred with steroid/antibiotic combination drugs which can usually be attributed to either the steroid component or the antibiotic component. The following adverse effects have been reported following use of topical ophthalmic dexamethasone or tobramycin.

 

	Dexamethasone	Tobramycin
System Organ Classification	Adverse reactions
Infections and infestations	Rare: eye infection (exacerbation or secondary)	Very rare: eye infection (secondary)
Endocrine disorders	Very rare: adrenal suppression Unknown: Cushing's syndrome, adrenal suppression (see section 4.4)
Eye disorders	Rare: visual acuity reduced, glaucoma, visual field defect, cataract subcapsular Unknown: Vision, blurred (see also section 4.4)	Uncommon: eye irritation, ocular hyperaemia, vision blurred Rare: eyelid oedema, eyelids pruritus, eye pain (periorbital)
General disorders and administration site conditions	Rare: impaired healing
Investigations	Uncommon: intraocular pressure increased
Injury, poisoning and procedural complications	Rare: optic nerve injury Very rare: corneal perforation
Immune system disorders		Uncommon: hypersensitivity (local)
Skin and subcutaneous tissue disorders		Uncommon: erythema (periorbital)

 

A topical overdose is not likely to occur or to be associated with toxicity.

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

Due to the characteristics of this preparation, no toxic effects are to be expected with an ocular overdose of this product, or in the event of accidental ingestion of the contents of one bottle or tube. Treatment of an accidental ingestion is symptomatic and supportive.

Pharmacotherapeutic group: corticosteroids and anti-infectives in combination

ATC code: S 01 CA 01

 

Mode of Action

The preparation contains tobramycin, a rapidly bactericidal aminoglycoside antibiotic.  It exerts its primary effect on bacterial cells by inhibiting polypeptide assembly and synthesis on the ribosome.

 

Mechanism of resistance

Resistance to tobramycin occurs by several different mechanisms including (1) alterations of the ribosomal subunit within the bacterial cell; (2) interference with the transport of tobramycin into the cell, and (3) inactivation of tobramycin by an array of adenylylating, phosphorylating, and acetylating enzymes. Genetic information for production of inactivating enzymes may be carried on the bacterial chromosome or on plasmids. Cross resistance to other aminoglycosides may occur.

 

Breakpoints

The breakpoints and the in vitro spectrum as mentioned below are based on systemic use. These breakpoints might not be applicable on topical ocular use of the medicinal product as higher concentrations are obtained locally and the local physical/chemical circumstances can influence the activity of the product on the site of administration.  In accordance with EUCAST, the following breakpoints are defined for tobramycin:

 

•        Enterobacteriaceae           S ≤ 2 mg/l, R > 4 mg/l

•        Pseudomonas spp.          S ≤ 4 mg/l, R > 4 mg/l

•        Staphylococcus spp.        S ≤ 1 mg/l, R > 1 mg/l

•        Not species-related          S ≤ 2 mg/l, R > 4 mg/l

 

PK/PD relationschip

 

A specific PK/PD relationship has not been established for Tobradex. Dexamethasone has

demonstrated dose-independent pharmacokinetics in published animal studies.

 

Published in vitro and in vivo studies have shown that tobramycin features a prolonged postantibiotic

effect, which effectively suppresses bacterial growth despite low serum

concentrations. Systemic administration studies of tobramycin have reported higher

maximum concentrations with once daily compared to multiple daily dosing regimens.

However, the weight of current evidence suggests that once daily systemic dosing is equally

as efficacious as multiple-daily dosing. Tobramycin exhibits a concentration-dependent

antimicrobial kill and greater efficacy with increasing levels of antibiotic above the MIC or

minimum bactericidal concentration (MBC).

 

Clinical efficacy against specific pathogens

 

The information listed below gives only an approximate guidance on probabilities whether microorganisms will be susceptible to tobramycin in this medicine. Bacterial species that have been recovered from external infections of the eye such as observed in conjunctivitis are presented here.

 

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 tobramycin in at least some types of infections is questionable.

 

COMMONLY SUSCEPTIBLE SPECIES

Aerobic Gram-positive microorganisms

Corynebacterium species

Staphylococcus aureus (methicillin susceptible)

Aerobic Gram-negative microorganisms

Enterobacter cloacae

Klebsiella oxytoca

Moraxella catarrhalis

Neisseria meningitidis

Pseudomonas aeruginosa

Serratia marescens

 

Antibacterial activity against other relevant pathogens

 

SPECIES FOR WHICH ACQUIRED RESISTANCE MIGHT BE A PROBLEM   Aerobic Gram-positive microorganisms Corynebacterium diphtheriae Staphylococcus aureus (methicillin resistant) Staphylococcus, other coagulase-negative spp. (methicillin resistant)   Aerobic Gram-negative microorganisms Neisseria gonorrhoeae     INHERENTLY RESISTANT ORGANISMS

Aerobic Gram-positive microorganisms

Streptococcus pneumoniae

Streptococcus pyogenes

Aerobic Gram-negative microorganisms

Haemophilus influenzae

Anaerobic Bacteria

Propionibacterium acnes   Other Chlamydia trachomatis

 

 

 

 

Dexamethasone is a moderately powerful corticosteroid, which has a good penetration in the 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.

 

Data from clinical studies

 

Cumulative safety data from clinical studies are presented in Section 4.8.

 

Paediatric population

The safety and efficacy of TOBRADEX eye drops and eye ointment in children have been established by broad clinical experience, but only limited data are available. In a clinical study of TOBRADEX suspension for the treatment of bacterial conjunctivitis, 29 paediatric patients, ranging in age from 1 to 17 years, were treated with 1 or 2 drops of TOBRADEX every 4 or 6 hours for 5 or 7 days. In this study, differences in the safety profile between adult and paediatric patients were not observed. See section 4.2 and 4.4 for more information on pediatric use.

Dexamethasone

The studies conducted with TOBRADEX eye drops, suspension have demonstrated that the systemic exposure to dexamethasone is low after topical eye use. The maximum plasma concentrations ranged between 220-888 pg/ml (medium values 555 ± 217 pg/ml) after the instillation of one drop of TOBRADEX in each eye, 4 times a day, for two consecutive days.

 

Dexamethasone is eliminated through the metabolism. Approximate 60% of the dose is recovered in urine as 6-β-hydroxydexamethasone. Unmodified dexamethasone is not recovered in urine. The plasma half-life through elimination is relatively short, 3-4 hours. Dexamethasone binds to the serum albumin approximately 77-84%. The clearance varies from 0.111 to 0.225 l/hour and kg, and the distribution volume varies from 0.576 to 1.15 l/kg. The oral bioavailability of dexamethasone is approximately 70%.

 

Tobramycin

The studies conducted on TOBRADEX eye drops, suspension have shown that the systemic exposure to tobramycin is low after topical ocular use. The plasma concentrations of tobramycin could not be determined in 9 of 12 patients to whom one drop of TOBRADEX has been administered, 4 times a day, for two consecutive days. The highest plasma concentration that could be measured was 0.25 μg/ml, a value that is 8 times smaller than the 2 μg/ml concentration known to be under the threshold associated with the risk of nephrotoxicity.

 

Tobramycin is rapidly excreted in large quantities in the urine through glomerular filtration, mainly unmodified. The plasma half-life is approx. 2 hours, with a 0.04 l/hour and kg clearance and a distribution volume of 0.26 l/kg. Binding of tobramycin to plasma albumin is low, less than10%. The oral bioavailability is low (<1%).

 

Effects in conventional non-clinical studies of repeated dose toxicity were observed only at exposures considered sufficiently in excess of the maximum human exposure after topical application, indicating little relevance to clinical use.

 

Non-clinical data reveal no special hazard for humans based on conventional studies of genotoxicity. No studies have been conducted to evaluate the carcinogenic potential of dexamethasone.

Tobramycin crosses the placenta into the foetal circulation and amniotic fluid. Animal studies with maternal systemic administration of high doses of tobramycin during organogenesis have been reported to result in renal toxicity in foetuses. Other studies performed in rats and rabbits with tobramycin at doses up to 100 mg/kg/day parenterally (> 400-times the maximum clinical dose) revealed no evidence of  harm to the foetus.

 

Corticosteroids have been found to be teratogenic in animal studies. Ocular administration of a 0.1% dexamethasone preparation to pregnant rabbits resulted in increased incidences of foetal anomalies. Foetal growth retardation and increased mortality rates have been observed in rats with chronic dexamethasone therapy.

Eye ointment:

Chlorobutanol, anhydrous

Liquid paraffin

White soft paraffin

No specific incompatibility studies with TOBRADEX have been undertaken.

2 years Discard 4 weeks after first opening.

Eye ointment: Do not store above 25°C. Do not refrigerate.

 

Eye ointment: Tobradex 3 mg/g + 1 mg/g eye ointment is a white to off-white homogeneous ointment, supplied in an aluminum tube of 3,5 g with screw cap.

 

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