Special Warning : אזהרת שימוש

4.4 Special warnings and precautions for use
General Warnings
Tobramycin should be used with caution in patients with known or suspected renal, auditory, vestibular or neuromuscular dysfunction, or with severe, active haemoptysis.
Renal and eighth cranial nerve function should be closely monitored in patients with known or suspected renal impairment and also in those whose renal function is initially normal but who develop signs of renal dysfunction during therapy. Evidence of impairment in renal, vestibular and/or auditory function requires discontinuation of the drug or dosage adjustment.
The serum concentration of tobramycin should only be monitored through venipuncture and not finger prick blood sampling which is a non validated dosing method. It has been observed that contamination of the skin of the fingers from the preparation and nebulisation of tobramycin may lead to falsely increased serum levels of the drug. This contamination cannot be completely avoided by hand washing before testing.

Bronchospasm
Bronchospasm can occur following inhalation of medicinal products and has been reported with nebulised tobramycin. The first dose of Bramitob should be given under medical supervision, using a pre-nebulisation bronchodilator if this is already part of the current treatment regimen for the patient. FEV1 (forced expiratory volume) should be measured before and after nebulisation.
If there is evidence of therapy-induced bronchospasm in a patient not receiving a bronchodilator, the test should be repeated on a separate occasion, using a bronchodilator. Onset of bronchospasm in the presence of bronchodilator therapy may indicate an allergic reaction. Should an allergic reaction be suspected, Bramitob should be discontinued. Bronchospasm should be treated as clinically appropriate.


Neuromuscular disorders
Tobramycin should be used with great caution in patients with neuromuscular disorders, such as parkinsonism or other conditions characterised by myasthenia, including myasthenia gravis, as aminoglycosides may worsen muscular weakness due to a potential curare-like effect on the neuromuscular function.

Nephrotoxicity
Although nephrotoxicity has been associated with parenteral aminoglycoside therapy, there was no evidence of nephrotoxicity during clinical trials with tobramycin. The product should be used with caution in patients with known or suspected renal dysfunction and tobramycin serum concentrations should be monitored, e.g. serum level assays after two or three doses should be performed, so that the dosage could be adjusted if necessary, and also at three to four day intervals during therapy. In the event of changing renal function, more frequent serum levels should be obtained and the dosage or dosage intervals adjusted. Patients with severe renal impairment, i.e.
serum creatinine > 2 mg/dl (176.8 µmol/l) were not included in the clinical studies.
Current clinical practice recommends that baseline renal function should be assessed.
Furthermore, the renal function should be periodically reassessed, by regularly monitoring urea and creatinine levels at least every 6 full cycles of therapy with tobramycin (180-day treatment with nebulised tobramycin). If there is evidence of nephrotoxicity, therapy with tobramycin should be discontinued until the drug minimum serum concentrations fall below 2 μg/ml.
Tobramycin therapy may then be resumed following medical advice. Patients receiving concomitant parenteral aminoglycoside therapy should be strictly monitored, due to the risk of cumulative toxicity.


Monitoring of renal function is particular important in elderly patients who may have reduced renal function that may not be evident in the results of routine screening tests, such as blood urea or serum creatinine. A creatinine clearance determination may be more useful.
Urine should be examined for increased excretion of protein, cells and casts. Serum creatinine or creatinine clearance (preferred over blood urea) should be measured periodically.

Ototoxicity
Ototoxicity, manifested as both auditory and vestibular toxicity has been reported with the parenteral aminoglycosides. Vestibular toxicity may be manifested by vertigo, ataxia or dizziness.

During controlled clinical studies with tobramycin, modest hypoacusia and vertigo were observed, while with other nebulised tobramycin containing medicines auditory toxicity, as measured by complaints of hearing loss or by audiometric evaluations, did not occur during controlled clinical studies.

In open label studies and post-marketing experience, some patients with a history of prolonged previous or concomitant use of intravenous aminoglycosides have experienced hearing loss.

The physician should consider the possibility that aminoglycosides may cause vestibular and cochlear toxicity and should assess auditory function throughout the treatment period with Bramitob. In patients with a predisposing risk due to previous prolonged systemic therapy with aminoglycosides, it may be necessary to consider audiological assessment before starting therapy with tobramycin. The occurrence of tinnitus warrants caution, since it represents an ototoxic symptom. If the patient reports about tinnitus or hearing loss during the therapy with aminoglycosides, the physician should consider whether audiologic tests are necessary. When feasible, it is recommended that serial audiograms are performed in patients on continuous therapy, which are at particular high risk of ototoxicity. Patients receiving concomitant parenteral therapy with aminoglycosides should be monitored as clinically appropriate, taking into account the risk of cumulative toxicity.

Haemoptysis
Inhalation of nebulised solutions may induce a cough reflex. The use of nebulised Bramitob in patients with active, severe haemoptysis should be undertaken only if the benefits of treatment are considered to outweigh the risks of inducing further haemorrhage.

Microbial Resistance
In clinical studies, some patients treated with nebulised tobramycin showed an increase in aminoglycoside Minimum Inhibitory Concentrations for P. aeruginosa isolates tested. There is a theoretical risk that patients being treated with nebulised tobramycin may develop P. aeruginosa isolates resistant to intravenous tobramycin (see section 5.1 Pharmacodynamic properties). In clinical trials there is no data in patients with Burkholderia cepacia infections.

For information related to administration during pregnancy and lactation see section 4.6 “Pregnancy and lactation”.

Effects on Driving

4.7 Effects on ability to drive and use machines
No studies on the effect on the ability to drive and use machines have been performed.
On the basis of reported adverse drug reactions, tobramycin is presumed to be unlikely to produce an effect on ability to drive and use machinery.
Nevertheless, since dizziness and/or vertigo may occur, patients who are going to drive or use machinery should be alerted.