Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2022 Publisher: TEVA UK Limited, Brampton Road, Hampden Park, Eastbourne, East Sussex BN22 9AG, UNITED KINGDOM
Pharmacotherapeutic group: Aminoglycoside Antibacterials
ATC code: J01GB01
Tobramycin is an aminoglycoside antibiotic produced by Streptomyces tenebrarius. It acts primarily by disrupting protein synthesis leading to altered cell membrane permeability, progressive disruption of the cell envelope and eventual cell death. It is bactericidal at concentrations equal to or slightly greater than inhibitory concentrations.
Established susceptibility breakpoints for parenteral administration of tobramycin are inappropriate in the aerosolised administration of the medicinal product.
Cystic fibrosis (CF) sputum exhibits an inhibitory action on the local biological activity of nebulised aminoglycosides. This necessitates sputum concentrations of aerosolised tobramycin to be around 10 and 25-fold above the Minimum Inhibitory Concentration (MIC) for, respectively, P. aeruginosa growth suppression and bactericidal activity. In controlled clinical trials, 97% of patients receiving inhaled tobramycin achieved sputum concentrations 10 fold the highest P. aeruginosa MIC cultured from the patient and 95% of patients receiving inhaled tobramycin achieved 25 fold the highest MIC. Clinical benefit is still achieved in a majority of patients who culture strains with MIC values above the parenteral breakpoint.
In the absence of conventional susceptibility breakpoints for the nebulised route of administration, caution must be exercised in defining organisms as susceptible or insusceptible to nebulised tobramycin. However, clinical studies showed that a microbiological report indicating in vitro drug resistance did not necessarily preclude a clinical benefit for the patient.
Most patients with P. aeruginosa isolates with tobramycin MICs <128 µg/mL at baseline showed improved lung function following treatment with inhaled tobramycin. Patients with a P. aeruginosa isolate with a MIC ≥128 µg/mL at baseline are less likely to show a clinical response. However, 7 of 13 patients (54%) in the placebo-controlled trials who acquired isolates with MICs ≥128 µg/mL while using inhaled tobramycin had improvement in pulmonary function.
Over the entire 96 week duration of the extension studies, the tobramycin MIC50 for P. aeruginosa increased from 1 to 2 µg/mL and the MIC90 increased from 8 to 32 µg/mL.
Based upon in vitro data and/or clinical trial experience, the organisms associated with pulmonary infections in CF may be expected to respond to inhaled tobramycin therapy as follows:
| Susceptible | Pseudomonas aeruginosa Haemophilus influenzae Staphylococcus aureus |
| Insusceptible | Burkholderia cepacia Stenotrophomonas maltophilia Alcaligenes xylosoxidans |
In clinical studies, treatment with inhaled tobramycin showed a small but clear increase in tobramycin, amikacin and gentamycin MIC for P. aeruginosa isolates tested. Each additional 6 months of treatment resulted in incremental increases similar in magnitude to that observed in the 6 months of controlled studies. The most prevalent aminoglycoside resistance mechanism seen in P. aeruginosa isolated from chronically infected CF patients is impermeability, defined by a general lack of susceptibility to all aminoglycosides. P. aeruginosa isolated from CF patients has also been shown to exhibit adaptive aminoglycoside resistance that is characterised by a reversion to susceptibility when the antibiotic is removed.
There is no evidence that patients treated for up to 18 months with inhaled tobramycin were at a greater risk for acquiring B. cepacia, S. maltophilia or A. xylosoxidans, than would be expected in patients not treated with tobramycin. Aspergillus species were more frequently recovered from the sputum of patients who received tobramycin; however, clinical sequelae such as Allergic Bronchopulmonary Aspergillosis (ABPA) were reported rarely and with similar frequency as in the control group.
There are insufficient clinical safety and efficacy data in children <6 years of age.
In an open-label uncontrolled study, 88 patients with CF (37 patients between 6 months and 6 years, 41 patients between 6 and 18 years of age and 10 patients above 18 years of age) with early (non-chronic) P. aeruginosa infection were treated for 28 days with tobramycin. After 28 days, patients were randomised 1:1 to either stop (n=45) or to receive a further 28 days treatment (n=43).
Primary outcome was the median time to recurrence of P. aeruginosa (any strain) which was 26.1 and 25.8 months for the 28-day and 56-day groups, respectively. It was found that 93 % and 92 % of the patients were free of P. aeruginosa infection 1 month after the end of treatment in the 28-day and 56-day groups, respectively. The use of tobramycin with a dosing regimen longer than 28 days continuous treatment is not approved.
In a double-blind, randomized, placebo-controlled trial, 51 patients aged 3 months to less than 7 years with a confirmed diagnosis of CF and an early colonization with P. aeruginosa (defined as: either first positive culture overall or first positive culture after at least a 1-year history of negative cultures) were treated with tobramycin 300 mg/5 mL or placebo, both inhaled via a nebuliser (PARI LC PLUS) twice daily for 28 days. Patients who were treated with anti-pseudomonal therapy in the previous year were excluded. A total of 26 patients were randomized to receive tobramycin and 25 patients to placebo. The primary outcome was based on the proportion of patients free from P. aeruginosa colonisation assessed by sputum/throat swab culture after completion of a 28-day treatment period which was 84.6% (22 out of 26 patients) for the tobramycin group and 24% (6 out of 25 patients) for the placebo group (p<0.001). The frequency, type and severity of the observed adverse events in children <7 years of age were consistent with the known safety profile of tobramycin.
The use of tobramycin is not indicated in children <6 years of age (see section 4.2 Posology and method of administration).
Two identically designed, double-blind, randomised, placebo-controlled, parallel group, 24-week clinical studies (Study 1 and Study 2) were conducted in cystic fibrosis patients with P. aeruginosa to support original registration which took place in 1999. These studies enrolled 520 subjects who had a baseline FEV1 of between 25% and 75% of their predicted normal value. Patients who were less than six years of age, or who had a baseline creatinine of >2 mg/dL or who had Burkholderia cepacia isolated from sputum were excluded. In these clinical studies, 258 patients received tobramycin therapy on an outpatient basis using a hand-held PARI LC PLUS Reusable Nebuliser with a DeVilbiss Pulmo-Aide compressor.
In each study, tobramycin-treated patients experienced significant improvement in pulmonary function and significant reduction in the number of P. aeruginosa colony forming units (CFUs) in sputum during the on-drug periods. The mean FEV1 remained above baseline in the 28-day off-drug periods, although it reversed somewhat on most occasions. Sputum bacterial density returned to baseline during the off drug periods. Reductions in sputum bacterial density were smaller in each successive cycle.
Patients treated with tobramycin experienced fewer hospitalisation days and required fewer days of parenteral anti-pseudomonal antibiotics on average, compared with placebo patients.
In open label extensions to the studies 1 and 2, there were 396 patients of the 464 who completed either of the two 24 week double blind studies. In total, 313, 264 and 120 patients completed treatment with tobramycin for 48, 72 and 96 weeks respectively. The rate of lung function decline was significantly lower following initiation of tobramycin therapy than that observed among patients receiving placebo during the double blind randomised treatment period. The estimated slope in the regression model of lung function decline was -6.52% during the blinded placebo treatment and -2.53% during tobramycin treatment (p=0.0001).
Tobramycin is a cationic polar molecule that does not readily cross epithelial membranes. The systemic exposure to tobramycin after inhalation is expected to result from pulmonary absorption of the dose fraction delivered to the lungs as tobramycin is not absorbed to any appreciable extent when administered via the oral route. The bioavailability of tobramycin may vary because of individual differences in nebuliser performance and airway pathology.
Ten minutes after the first inhalation of tobramycin 300 mg, the average sputum concentrations of tobramycin was 1,237 µg/g (range: 35 to 7,414 µg/g). Tobramycin does not accumulate in sputum; after 20 weeks of therapy with the tobramycin regimen, the average sputum concentration of tobramycin 10 minutes after inhalation was 1,154 µg/g (range: 39 to 8,085 µg/g). High variability of sputum tobramycin concentrations was observed. Two hours after inhalation, sputum concentration declined to approximately 14% of the tobramycin levels measured at 10 minutes after inhalation.
The mean serum concentration of tobramycin 1 hour after inhalation of a single 300 mg dose of tobramycin by CF patients, was 0.95 µg/mL (range: below limit of quantitation [BLQ] - 3.62 µg/mL). After 20 weeks of therapy, the mean serum tobramycin concentration, 1 hour after dosing, was 1.05 µg/mL (range: BLQ – 3.41 µg/mL). For comparison, the peak concentrations after intravenous or intramuscular administration of a single tobramycin dose of 1.5 to 2 mg/kg typically range from 4 to 12 µg/mL.
Following administration, tobramycin remains concentrated primarily in the airways. Less than 10% of tobramycin is bound to plasma proteins.
Tobramycin is not metabolised and is primarily excreted unchanged in the urine.
The elimination of tobramycin administered by the inhalation route has not been studied.
Following intravenous administration, tobramycin is eliminated principally by glomerular filtration of the unchanged compound. The apparent terminal half-life of tobramycin in serum after inhalation of a 300 mg single dose of tobramycin was 3 hours in cystic fibrosis patients.
Renal function is expected to affect the exposure to tobramycin, however data are not available as patients with serum creatinine 2 mg/dL (176.8 µmol/L) or more or blood urea nitrogen (BUN) 40 mg/dL or more were not included in clinical studies.
Unabsorbed tobramycin following tobramycin administration is probably eliminated primarily in expectorated sputum.
Pre-clinical data reveal that the main hazard for humans, based on studies of safety pharmacology, repeated dose toxicity, genotoxicity or toxicity to reproduction, consists of renal toxicity and ototoxicity. In repeated dose toxicity studies, target organs of toxicity are the kidneys and vestibular/cochlear functions. In general, toxicity is seen at higher systemic tobramycin levels than are achievable by inhalation at the recommended clinical dose.
Carcinogenicity studies with inhaled tobramycin do not increase the incidence of any variety of tumour. Tobramycin showed no genotoxic potential in a battery of genotoxicity tests.
No reproduction toxicology studies have been conducted with tobramycin administered by inhalation, but subcutaneous administration at doses of 100 mg/kg/day in rats and the maximum tolerated dose of 20 mg/kg/day in rabbits, during organogenesis, was not teratogenic. Teratogenicity could not be assessed at higher parenteral doses (greater than or equal to 40 mg/kg/day) in rabbits as they induced maternal toxicity and abortion. Ototoxicity was not evaluated in offspring during nonclinical reproduction toxicity studies with tobramycin.
Based on available data from animals, a risk of toxicity (e.g. ototoxicity) at prenatal exposure levels cannot be excluded.
Subcutaneous administration of up to 100 mg/kg of tobramycin did not affect mating behaviour or cause impairment of fertility in male or female rats.
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