"The US Food and Drug Administration (FDA) is investigating the "rare but serious" risk for slowed or difficult breathing in children 17 and younger treated with the opioid analgesic tramadol.
"This risk may be increased in children tr"...
TOBI is specifically formulated for administration by inhalation. When inhaled, tobramycin is concentrated in the airways.
TOBI contains tobramycin, a cationic polar molecule that does not readily cross epithelial membranes.1 The bioavailability of TOBI may vary because of individual differences in nebulizer performance and airway pathology.2 Following administration of TOBI, tobramycin remains concentrated primarily in the airways.
Ten minutes after inhalation of the first 300-mg dose of TOBI, the average concentration of tobramycin was 1237 mcg/g (ranging from 35 to 7417 mcg/g) in sputum. Tobramycin does not accumulate in sputum; after 20 weeks of therapy with the TOBI regimen, the average concentration of tobramycin at ten minutes after inhalation was 1154 mcg/g (ranging from 39 to 8085 mcg/g) in sputum. High variability of tobramycin concentration in sputum was observed. Two hours after inhalation, sputum concentrations declined to approximately 14% of tobramycin levels at ten minutes after inhalation.
The average serum concentration of tobramycin one hour after inhalation of a single 300-mg dose of TOBI by cystic fibrosis patients was 0.95 mcg/mL. After 20 weeks of therapy on the TOBI regimen, the average serum tobramycin concentration one hour after dosing was 1.05 mcg/mL.
The elimination half-life of tobramycin from serum is approximately 2 hours after intravenous (IV) administration. Assuming tobramycin absorbed following inhalation behaves similarly to tobramycin following IV administration, systemically absorbed tobramycin is eliminated principally by glomerular filtration. Unabsorbed tobramycin, following TOBI administration, is probably eliminated primarily in expectorated sputum.
Tobramycin is an aminoglycoside antibiotic produced by Streptomyces tenebrarius.1 It acts primarily by disrupting protein synthesis, leading to altered cell membrane permeability, progressive disruption of the cell envelope, and eventual cell death.3
Tobramycin has in vitro activity against a wide range of gram-negative organisms including Pseudomonas aeruginosa. It is bactericidal at concentrations equal to or slightly greater than inhibitory concentrations.
A single sputum sample from a cystic fibrosis patient may contain multiple morphotypes of Pseudomonas aeruginosa and each morphotype may have a different level of in vitro susceptibility to tobramycin. Treatment for 6 months with TOBI in two clinical studies did not affect the susceptibility of the majority of P. aeruginosa isolates tested; however, increased minimum inhibitory concentrations (MICs) were noted in some patients. The clinical significance of this information has not been clearly established in the treatment of P. aeruginosa in cystic fibrosis patients. For additional information regarding the effects of TOBI on P. aeruginosa MIC values and bacterial sputum density, please refer to the CLINICAL STUDIES section.
The in vitro antimicrobial susceptibility test methods used for parenteral tobramycin therapy can be used to monitor the susceptibility of P. aeruginosa isolated from cystic fibrosis patients. If decreased susceptibility is noted, the results should be reported to the clinician.
Susceptibility breakpoints established for parenteral administration of tobramycin do not apply to aerosolized administration of TOBI. The relationship between in vitro susceptibility test results and clinical outcome with TOBI therapy is not clear.
Two identically designed, double-blind, randomized, placebo-controlled, parallel group, 24-week clinical studies (Study 1 and Study 2) at a total of 69 cystic fibrosis centers in the United States were conducted in cystic fibrosis patients with P. aeruginosa. Subjects who were less than 6 years of age, had a baseline creatinine of > 2 mg/dL, or had Burkholderia cepacia isolated from sputum were excluded. All subjects had baseline FEV1 % predicted between 25% and 75%. In these clinical studies, 258 patients received TOBI therapy on an outpatient basis (see Table 2) using a hand-held PARI LC PLUS Reusable Nebulizer with a DeVilbiss Pulmo-Aide compressor.
Table 2: Dosing Regimens in Clinical Studies
|Cycle 1||Cycle 2||Cycle 3|
|28 days||28 days||28 days||28 days||28 days||28 days|
|TOBI||No drug||TOBI||No drug||TOBI||No drug|
|300 mg||300 mg||300 mg|
|placebo||No drug||placebo||No drug||placebo||No drug|
All patients received either TOBI or placebo (saline with 1.25 mg quinine for flavoring) in addition to standard treatment recommended for cystic fibrosis patients, which included oral and parenteral antipseudomonal therapy, β2-agonists, cromolyn, inhaled steroids, and airway clearance techniques. In addition, approximately 77% of patients were concurrently treated with dornase alfa (PULMOZYME, Genentech).
In each study, TOBI-treated patients experienced significant improvement in pulmonary function. Improvement was demonstrated in the TOBI group in Study 1 by an average increase in FEV1 % predicted of about 11% relative to baseline (Week 0) during 24 weeks compared to no average change in placebo patients. In Study 2, TOBI-treated patients had an average increase of about 7% compared to an average decrease of about 1% in placebo patients. Figure 1 shows the average relative change in FEV1% predicted over 24 weeks for both studies.
Figure 1: Relative Change From Baseline in FEV1%
In each study, TOBI therapy resulted in a significant reduction in the number of P. aeruginosa colony forming units (CFUs) in sputum during the on-drug periods. Sputum bacterial density returned to baseline during the off-drug periods. Reductions in sputum bacterial density were smaller in each successive cycle (see Figure 2).
Figure 2: Absolute Change
From Baseline in Log10 CFUs
Patients treated with TOBI were hospitalized for an average of 5.1 days compared to 8.1 days for placebo patients. Patients treated with TOBI required an average of 9.6 days of parenteral antipseudomonal antibiotic treatment compared to 14.1 days for placebo patients. During the 6 months of treatment, 40% of TOBI patients and 53% of placebo patients were treated with parenteral antipseudomonal antibiotics.
The relationship between in vitro susceptibility test results and clinical outcome with TOBI therapy is not clear. However, 4 TOBI patients who began the clinical trial with P. aeruginosa isolates having MIC values ≥ 128 mcg/mL did not experience an improvement in FEV1 or a decrease in sputum bacterial density.
Treatment with TOBI did not affect the susceptibility of the majority of P. aeruginosa isolates during the 6-month studies. However, some P. aeruginosa isolates did exhibit increased tobramycin MICs. The percentage of patients with P. aeruginosa isolates with tobramycin MICs ≥ 16 mcg/mL was 13% at the beginning, and 23% at the end of 6 months of the TOBI regimen.
1. Neu HC. Tobramycin: an overview. [Review]. J Infect Dis 1976; Suppl 134:S3-19.
2. Weber A, Smith A, Williams-Warren J et al. Nebulizer delivery of tobramycin to the lower respiratory tract. Pediatr Pulmonol 1994; 17 (5):331-9.
3. Bryan LE. Aminoglycoside resistance. Bryan LE, Ed. Antimicrobial drug resistance. Orlando, FL: Academic Press, 1984: 241-77.
Last reviewed on RxList: 10/19/2015
This monograph has been modified to include the generic and brand name in many instances.
Additional Tobi Information
Tobi - User Reviews
Tobi User Reviews
Now you can gain knowledge and insight about a drug treatment with Patient Discussions.
Report Problems to the Food and Drug Administration
Find out what women really need.