Firma Chun Cheong
Full Prescribing Info
Ophthalmic solution: 1 ml solution contains 3 mg tobramycin.
Excipient with known effect: 1 ml solution contains 0.1 mg benzalkonium chloride.
Ophthalmic ointment: 1 g eye ointment contains 3 mg tobramycin.
Excipients/Inactive Ingredients: Ophthalmic solution: Benzalkonium chloride, Boric acid, Sodium sulphate anhydrous, Sodium chloride, Tyloxapol, Sulphuric acid and/or sodium hydroxide, Purified water.
Ophthalmic ointment: Anhydrous chlorobutanol, Mineral oil, White petrolatum.
Pharmacotherapeutic group: ophthalmologicals; anti-infectives. ATC code: S01A A12.
Pharmacology: Pharmacodynamics: 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 as follows 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 as follows 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.
COMMONLY SUSCEPTIBLE SPECIES: Aerobic Gram-positive microorganisms: Bacillus megaterium, Bacillus pumilus, Corynebacterium accolens, Corynebacterium bovis, Corynebacterium macginleyi, Corynebacterium pseudodiphtheriticum, Kocuria kristinae, Staphylococcus aureus (methicillin susceptible - MSSA), Staphylococcus epidermidis (coagulase-positive and -negative), Staphylococcus haemolyticus (methicillin susceptible - MSSH), Streptococci (including some of the group A beta-hemolytic species, some nonhemolytic species, and some Streptococcus pneumonia).
Aerobic Gram-negative microorganisms: Acinetobacter calcoaceticus, Enterobacter aerogenes, Escherichia coli, Acinetobacter junii, Acinetobacter ursingii, Citrobacter koseri, H. aegyptius, Haemophilus influenzae, Klebsiella oxytoca, Klebsiella pneumoniae, Morganella morganii, Moraxella catarrhalis, Moraxella oslonensis, Moraxella lacunata, Some Neisseria species, Proteus mirabilis, Most Proteus vulgaris strains, Pseudomonas aeruginosa, Serratia liquifaciens.
Anti-bacterial activity against other relevant pathogens: SPECIES FOR WHICH ACQUIRED RESISTANCE MIGHT BE A PROBLEM: Acinetobacter baumanii; Bacillus cereus; Bacillus thuringiensis; Kocuria rhizophila; Staphylococcus haemolyticus (methicillin resistant - MRSH); Staphylococcus, other coagulase-negative spp.; Serratia marcescens.
INHERENTLY RESISTANT ORGANISMS: Aerobic Gram-positive microorganisms: Enterococci faecalis, Staphylococcus aureus (methicillin resistant - MRSA), Streptococcus mitis, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus sanguis.
Aerobic Gram-negative microorganisms: Haemophilus influenzae, Stenotrophomonas maltophilia, Chryseobacterium indologenes, Burkholderia cepacia.
Anaerobic bacteria: Propionibacterium acnes.
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 Adverse Reactions.
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.
Pharmacokinetics: 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 µg/ml; tobramycin concentration in human eye after a single dose of TOBREX is 848 ± 674 µg/ml, 1 minute after dosing).
Tobramycin concentration in healthy human tears remains over MIC90 (16 µg/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.
Toxicology: Preclinical safety data: 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.
TOBREX Ophthalmic Solution and Ointment are topical antibiotic indicated in the treatment of external infections of the eye and its adnexa caused by susceptible bacteria. Appropriate monitoring of bacterial response to topical antibiotic therapy should accompany the use of TOBREX Ophthalmic Solution and Ointment. Clinical studies have shown tobramycin to be safe and effective for use in children.
Dosage/Direction for Use
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 Pharmacology: Pharmacodynamics under Actions. The safety and efficacy 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 a least 5 minutes should be allowed between successive applications. Eye ointments should be administered last.
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.
Hypersensitivity to the active substance or to any of the excipients listed in Description.
Hypersensitivity to aminoglycosides.
Special Precautions
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 Adverse Reactions).
Serious adverse reactions including neurotoxicity, ototoxicity and nephrotoxicity have occurred in patients receiving systemic tobramycin therapy. Caution is advised when using concomitant topical and systemic aminoglycosides and care should be taken to monitor total serum concentrations (see Adverse Reactions).
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.
Additionally, TOBREX eye drops contains benzalkonium chloride which may cause irritation and is known to discolour soft contact lenses. Avoid contact with soft contact lenses. Patients must be instructed to remove contact lenses prior to application of TOBREX and wait 15 minutes after application of the dose before reinsertion.
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.
Effects on ability to drive and use machines: TOBREX eye drops and eye 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.
Use In Pregnancy & Lactation
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 Pharmacology: Toxicology: Preclinical safety data under Actions).
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 previously 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 Pharmacology: Toxicology: Preclinical safety data under Actions.)
Adverse Reactions
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: See table.

Click on icon to see table/diagram/image

Description of selected adverse events: Sensitivity to topically administered aminoglycosides may occur in some patients (see Precautions).
If topical ocular tobramycin is administered concomitantly with systemic aminoglycoside antibiotics, care should be taken to monitor the total serum concentration (see Precautions).
Serious adverse reactions including neurotoxicity, ototoxicity and nephrotoxicity have occurred in patients receiving systemic tobramycin therapy (see Precautions).
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 Pharmacology: Pharmacodynamics under Actions. The safety and efficacy in children younger than 1 year of age have not been established, and no data are available (see Dosage & Administration).
Pediatric population: The frequency, type and severity of adverse reactions in children are expected to be the same as in adults.
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.
Drug Interactions
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.
Caution For Usage
Special precautions for disposal and other handling: No special requirements for disposal.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Incompatibilities: No specific incompatibility studies have been undertaken.
Shelf life: Discard 4 weeks after first opening.
ATC Classification
S01AA12 - tobramycin ; Belongs to the class of antibiotics. Used in the treatment of eye infections.
Ophth soln 0.3% (sterile) x 5 mL. Ophth oint 0.3% (sterile) x 3.5 g.
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