Pharmacotherapeutic group: corticosteroids and anti-infectives in combination. ATC code: S 01 CA 01.
Pharmacology: Pharmacodynamics: 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 relationship: 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 as follow 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 Adverse Reactions.
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 Dosage & Administration and Precautions for more information on paediatric use.
Pharmacokinetics: 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 than 10%. The oral bioavailability is low (<1%).
Toxicology: Preclinical safety data: 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.