TOBREX is indicated for the treatment of external infections of the eye and its adnexa, caused by bacteria sensitive to tobramycin, in particular those resistant to most other antibiotics, especially Pseudomonas aeruginosa, in adults and children aged 1 year and older (see section 5.1).

As with other antibiotics, appropriate monitoring of bacterial response to treatment should be performed.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Posology

-          In mild disease: 1 or 2 drops in the eye(s) every 4 hours, or a small amount of ointment 2 to 3 times per day.

-          In more severe infections: 2 drops in the eye(s) hourly or a small amount of ointment every 3 to 4 hours until improvement, following which treatment should be reduced prior to discontinuation.

The length of the treatment is dependent on the origin of the infection and may vary from a couple of days up to some weeks.

Paediatric population

TOBREX eye drops and eye ointment may be used in children 1 year of age and older at the same dose as in adults. Currently available data is described in section 5.1. The safety and efficacy of TOBREX eye drops and eye ointment in children younger than 1 year of age have not been established. No data are available.

Older people

No overall clinical differences in safety or efficacy have been observed between the elderly and other adult populations.

Use in hepatic and renal impairment

TOBREX eye drops and eye ointment have not been studied in these patient populations. However, due to low systemic absorption of tobramycin after topical administration of this product, dose adjustment is not necessary.

Method of administration

For ocular use.

TOBREX eye drops: after cap is removed from eye drops bottle, if tamper evident snap collar is loose, remove before using product.

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

In case of concomitant therapy with other topical ocular medicines, an interval of at least 5  minutes should be allowed between successive applications. Eye ointments should be administered last.

• For topical ophthalmic use only. Not for injection or ingestion.
• Cross-hypersensitivity with other aminoglycosides can occur. The possibility that patients who become sensitized to topical ocular tobramycin may also be sensitive to other topical and/or systemic aminoglycosides should be considered.
• 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 and other medications used (see section 4.8)
• Serious adverse reactions including neurotoxicity, ototoxicity and nephrotoxicity have occurred in patients receiving systemic aminoglycoside therapy. Caution is advised when TOBREX is used concomitantly with systemic aminoglycosides and care should be taken to monitor total serum concentrations (see section 4.8).
• Caution should be exercised when prescribing TOBREX 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.
• As with other antibiotic preparations, prolonged use of TOBREX may result in overgrowth of non-susceptible organisms, including fungi. If superinfection occurs, appropriate therapy should be initiated.
• 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 the product.
• This medicine contains 0,1 mg benzalkonium chloride in each ml. Benzalkonium chloride may be absorbed by soft contact lenses and may change the colour of the contact lenses. Patients should remove contact lenses before using this medicine and put them back 15 minutes afterwards. Benzalkonium chloride may also cause eye irritation, especially if the patient has dry eyes or a disorder of the cornea (the clear layer at the front of the eye).

• After application of TOBREX eye drops following measures are useful to reduce systemic absorption:

·         keep the eyelid closed for 2 minutes;

·         close the lachrymal duct with the finger for 2 minutes.

No interaction studies have been performed. No clinically relevant interactions have been described with topical ocular dosing of TOBREX.

Concomitant and/or sequential use of an aminoglycoside (tobramycin) 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.

Topical corticosteroids, when used in combination with tobramycin, may mask the clinical signs of bacterial, fungal, or viral infections and may suppress hypersensitivity reactions.

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

Pregnancy

There is no or limited data from the use of topical ocular tobramycin in pregnant women.

Human studies have not shown an association between the administration of tobramycin and malformations. 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.

Studies in animals have shown reproductive toxicity after systemic exposure and at dosages considered sufficiently in excess of the maximal human dose in therapeutic use derived from tobramycin eye drops so as to have limited clinical relevance (see Section 5.3).

Although systemic exposure to tobramycin from the topical route of administration is expected to be negligible, as a precautionary measure, it is preferable to avoid the use of Tobramycin during pregnancy. TOBREX should be used during pregnancy only if clearly needed

Breast-feeding

Minimal exposure of tobramycin in breast milk in lactating women was found after intravenous or intramuscular administration of up to 150 mg TID of tobramycin. Even though there is no specific systemic exposure data for tobramycin after ophthalmic administration, given the much smaller doses of these drugs administered topically to the eye compared to the systemic doses noted above with minimal transfer into breast milk, no effects on the breast fed newborn/infant are anticipated. Topical ocular tobramycin can be used during breast-feeding if the benefit to the mother is considered to outweigh the risk to the breast fed newborn/infant.

Fertility

Studies have not been performed to evaluate the effect of tobramycin administration on human or animal fertility. (see Section 5.3)

TOBREX eye drops and ointment have no or negligible influence on the ability to drive and use machines. As with any other eye preparation, 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 machinery.

Summary of the safety profile

In clinical trials, the most frequently reported adverse reactions were ocular hyperaemia and ocular discomfort, occurring in approximately 1.4% and 1.2% of patients.

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 were obtained from clinical trials and postmarketing spontaneous reports. The following adverse reactions were observed following ophthalmic use of TOBREX:

Description of selected adverse events

·         Sensitivity to topically administered aminoglycosides may occur in some patients (see section 4.4).

·         If topical ocular tobramycin is administered concomitantly with systemic aminoglycoside antibiotics, care should be taken to monitor the total serum concentration (see section 4.4).

·         Serious adverse reactions including neurotoxicity, ototoxicity and nephrotoxicity have occurred in patients receiving systemic tobramycin therapy (see section 4.4).

·         TOBREX may be used in children 1 year 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 1 year of age have not been established, and no data are available (see section 4.2). 

Pediatric population:

The frequency, type and severity of adverse reactions in children are expected to be the same as in adults.

To report any side effect(s):

·         Saudi Arabia

-          Saudi Food and Drug Authority National Pharmacovigilance Center (NPC):

o Fax: +966112057662

o Call NPC at +966-11-2038222, Exts: 2317-2356-2340.

o Toll free phone: 8002490000

o SFDA call center: 19999

o E-mail: npc.drug@sfda.gov.sa

o Website: https://ade.sfda.gov.sa

-          Patient Safety Department Novartis Consulting AG - Saudi Arabia:

o Toll Free Number: 8001240078

o Phone: +966112658100

o Fax: +966112658107

o Email: adverse.events@novartis.com

•    Other GCC States:

-  Please contact the relevant competent authority.

Due to the characteristics of this preparation, no toxic systemic effects are to be expected with the ophthalmic use of this product, with an ocular overdose of this product, or in the event of accidental ingestion of the contents of one bottle/tube.

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

Pharmacotherapeutic group: ophthalmologicals; anti-infectives, ATC code: S01A A12

Mechanism of action

Tobramycin is a potent, broad-spectrum, fast-working 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

•        Acinetobacter 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

Clinical efficacy against specific pathogens

The information listed below gives only an approximate guidance on probabilities whether microorganisms will be susceptible to tobramycin in TOBREX. Bacterial species that have been recovered from external ocular 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.

Bacterial susceptibility studies demonstrate that in some cases, microorganisms resistant to gentamicin retain susceptibility to tobramycin.

PK/PD relationship

A specific PK/PD relationship has not been established for TOBREX. Published in vitro and in vivo studies have shown that tobramycin features a prolonged post-antibiotic effect, which effectively suppresses bacterial growth despite low serum concentrations. 

Systemic administration studies 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).

Data from clinical studies  

Pharmacodynamic clinical trials of cumulative safety data from clinical studies are presented in section 4.8.

Elderly population

No overall clinical differences in safety or efficacy have been observed between the elderly and other adult populations.

Paediatric population

Over 600 paediatric patients were enrolled in 10 clinical studies with tobramycin eye drops or eye ointment for the treatment of bacterial conjunctivitis, blepharitis, or blepharoconjunctivitis. These patients ranged in age from 1 year to 18 years. Overall, the safety profile in paediatric patients was comparable to that of adult patients. For children younger than age 1, no recommendation on a posology can be made due to a lack of data.

Absorption

Tobramycin is poorly absorbed across rabbit cornea and conjunctiva and minimal amounts are absorbed into the eye after topical administration of tobramycin.

Additionally, systemic absorption of tobramycin is poor clinically after topical ocular administration of tobramycin products with similar concentration to TOBREX (0.3%).

The high concentration of tobramycin in TOBREX delivers tobramycin at the site of infection (ocular surface) at a concentration generally much higher than the MIC of the most resistant isolates (MICs > 64 mg/ml; tobramycin concentration in human eye after a single dose of TOBREX is 848 ± 674 mg/ml, 1 minute after dosing).

Tobramycin concentration in healthy human tears remains over MIC₉₀ (16 mg/ml as described for ocular isolates) at least up to 44 minutes post dosing of a treatment with TOBREX.

Distribution

The volume of distribution is 0.26 l/kg in man. Human plasma protein binding of tobramycin is low at less than 10%.

Biotransformation

Tobramycin is excreted in the urine primarily as unchanged drug.

Elimination

Tobramycin is excreted rapidly and extensively in the urine via glomerular filtration, primarily as unchanged drug. The plasma half-life is approximately two hours.  The reported systemic clearance in adult subjects with normal renal function ranged from of 0.05 – 0.1 L/hr/kg and decreased with decreased renal function.

Linearity/non-linearity

Ocular or systemic absorption with increasing dosing concentrations after topical ocular administration has not been tested. Therefore, the linearity of exposure with ocular dose could not be established.

Use in hepatic and renal impairment

TOBREX eye drops and eye ointment have not been studied in these patient populations. However, due to low systemic absorption of tobramycin after topical administration of this product, dose adjustment is not necessary.

Use in paediatrics

TOBREX may be used in paediatric patients (1 year of age and older) at the same dose as in adults. However, limited information is available in paediatric patients younger than 1 year of age.

Tobramycin is very poorly absorbed from the gastrointestinal tract. High parenterally administered doses of tobramycin have been reported to cause renal toxicity in rats and dogs, and ototoxicity in cats.

Preclinical studies have shown high systemic doses of tobramycin were administered using the intra-peritoneal (IP) route at 30 and 60 mg/kg to rats during periods of major organogenesis; which caused increases in glomerular density and the loss of cortical area within the kidney in the fetuses and in newborn rats. Similarly in other laboratory animals, aminoglycoside antibiotics are considered to be ototoxic. Prolonged systemic treatment of tobramycin in cats administered using the subcutaneous route at 20, 40 and 80 mg/kg/day for 30 weeks resulted in dose-dependent degeneration of hair cells and supporting sensory structures in the ear.  However, the human ear is now perceived as being anatomically more protected and thereby, less vulnerable to aminoglycoside-induced injury than with the animal models.

• Benzalkonium chloride
• Boric acid
• Anhydrous sodium sulphate
• Sodium chloride
• Tyloxapol
• Sulphuric acid and/or sodium hydroxide
• Purified water

No specific incompatibility studies have been undertaken.

Do not store above 30°C

TOBREX eye drops, solution is supplied in a 5 ml plastic dropper container (DROPTAINER®) with a screw cap.

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