2 years.
After first opening the single-dose container: use immediately.
In use shelf life: Bramitob bags (intact or opened) may be stored for up to 3 months at not more than 25°C.
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products in the nebuliser.
Sodium chloride
Sulphuric acid
Sodium hydroxide
Water for injections
In repeated dose toxicity studies, the target organs are the kidneys and vestibular/cochlear functions. In general, the signs and symptoms of nephrotoxicity and ototoxicity are seen at higher systemic tobramycin levels than are achievable by inhalation at the recommended clinical dose.
In preclinical studies, administration of inhaled tobramycin during up to 28 consecutive days determined modest, unspecific and fully reversible (on therapy discontinuation) signs of irritation in the respiratory tract, and signs of renal toxicity, at the highest doses.
No reproductive toxicology studies have been carried out with inhaled tobramycin, but subcutaneous administration of doses up to 100mg/kg/day during organogenesis in rats was not teratogenic. In rabbits, subcutaneous administration of doses of 20-40mg/kg caused maternal toxicity and abortions, but without evidence of any teratogenic signs.
Considering the data available from animals, a risk of toxicity (e.g. ototoxicity) at prenatal exposure levels cannot be excluded.
Tobramycin was not shown to be genotoxic.
Absorption and distribution
Following oral administration only 0.3-0.5% of the drug appears in urine to prove systemic absorption. After administration via nebuliser in 6 cystic fibrosis patients, mean absolute bioavailability was about 9.1% of the dose. Systemic absorption of tobramycin is very low when administered by aerosol inhalation, with a limited uptake of the inhaled drug into the systemic circulation, it is estimated that approximately 10% of the mass of drug initially nebulised is deposited in the lungs and the remaining 90% either remains in the nebuliser, is impacted on the oro-pharynx and swallowed, or is exhaled into the atmosphere.
Sputum concentrations: Ten minutes after inhalation of the first 300 mg dose of Bramitob, the average sputum concentration of tobramycin was 695.6 μg/g (range: 36 to 2,638 μg/g). Tobramycin does not accumulate in sputum; after 20 weeks of therapy with the Bramitob regimen, the average sputum concentration of tobramycin 10 minutes after inhalation was 716.9 μg/g (range: 40 to 2,530 μg/g). High variability of sputum tobramycin concentrations was observed. Two hours after inhalation, sputum concentrations declined to approximately 14% of tobramycin levels measured at 10 minutes after inhalation.
Serum concentrations: The median serum concentration of tobramycin 1 hour after inhalation of a single 300 mg dose of Bramitob by CF patients was 0.68 μg/mL (range: 0.06μg/mL - 1.89μg/mL). After 20 weeks of therapy on the tobramycin regimen, the median serum tobramycin concentration 1 hour after dosing was 1.05 μg/mL (range: BLQ- 3.41μg/mL).
Elimination
The elimination of tobramycin administered by the inhalation route has not been studied.
Following intravenous administration, systemically absorbed tobramycin is eliminated principally by glomerular filtration. The elimination half-life of tobramycin from serum is approximately 2 hours. Less than 10% of tobramycin is bound to plasma proteins.
Unabsorbed tobramycin following tobramycin administration is probably eliminated primarily in expectorated sputum.
July 2015
Chiesi Limited
333 Styal Road
Manchester
M22 5LG
UK
Store in a refrigerator (2-8°C).
Store in the original package in order to protect from light.
The solution of Bramitob single-dose container is normally yellowish; some variations in colour might be observed, which does not indicate any loss of activity if the product has been stored as recommended.
The medicinal product is supplied in 4ml single-dose polyethylene containers, in sealed foiled bags each holding 4 single-dose containers.
Pack sizes: 4, 16, 28 or 56 single-dose containers.
Not all pack sizes may be marketed.
PL 8829/0155
For single use only.
Use immediately after first opening the single-dose container. Discard the used single-dose container immediately.
Any waste material should be discarded after use.
Date of first authorisation: 1st June 2007
Date of last renewal: 23 March 2011
