Special Warning : אזהרת שימוש

4.4   Special warnings and precautions for use

Ototoxicity
Ototoxicity, manifested as both auditory toxicity (hearing loss) and vestibular toxicity, has been reported with parenteral aminoglycosides. Vestibular toxicity may be manifested by vertigo, ataxia, or dizziness. Tinnitus may be a sentinel symptom of ototoxicity, and therefore the onset of this symptom warrants caution.
Hearing loss and tinnitus were reported by patients in the TOBI Podhaler clinical studies (see section 4.8). Caution should be exercised when prescribing TOBI Podhaler to patients with known or suspected auditory or vestibular dysfunction.
In patients with any evidence of auditory dysfunction, or those with a predisposing risk, it may be necessary to consider audiological assessment before initiating TOBI Podhaler therapy.
Risk of ototoxicity due to mitochondrial DNA variants
Cases of ototoxicity with aminoglycosides have been observed in patients with certain variants in the mitochondrially encoded 12S rRNA gene (MT-RNR1), particularly the m.1555A>G variant.
Ototoxicity occurred in some patients even when their aminoglycoside serum levels were within the recommended range. In case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial DNA variant in the patient, it may be necessary to consider alternative treatments other than aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the severity of infection and lack of safe and effective alternative therapies.

If a patient reports tinnitus or hearing loss during TOBI Podhaler therapy the physician should consider referring them for audiological assessment.
See also “Monitoring of serum tobramycin concentrations” below.
Nephrotoxicity
Nephrotoxicity has been reported with the use of parenteral aminoglycosides. Nephrotoxicity was not observed during TOBI Podhaler clinical studies. Caution should be exercised when prescribing TOBI Podhaler to patients with known or suspected renal dysfunction.
Baseline renal function should be assessed. Urea and creatinine levels should be reassessed after every 6 complete cycles of TOBI Podhaler therapy.
See also section 4.2 and “Monitoring of serum tobramycin concentrations” below.
Monitoring of serum tobramycin concentrations
Patients with known or suspected auditory or renal dysfunction should be monitored for serum tobramycin concentrations. If oto- or nephrotoxicity occurs in a patient receiving TOBI Podhaler, tobramycin therapy should be discontinued until serum concentration falls below 2 μg/ml.
Serum concentrations greater than 12 μg/ml are associated with tobramycin toxicity and treatment should be discontinued if concentrations exceed this level.
The serum concentration of tobramycin should only be monitored through validated methods.
Finger prick blood sampling is not recommended due to the risk of contamination of the sample.
Bronchospasm
Bronchospasm can occur with inhalation of medicinal products and has been reported with TOBI Podhaler in clinical studies. Bronchospasm should be treated as medically appropriate.

The first dose of TOBI Podhaler should be given under supervision, after using a bronchodilator if this is part of the current regimen for the patient. FEV1 should be measured before and after inhalation of TOBI Podhaler.
If there is evidence of therapy-induced bronchospasm, the physician should carefully evaluate whether the benefits of continued use of TOBI Podhaler outweigh the risks to the patient. If an allergic response is suspected, TOBI Podhaler should be discontinued.
Cough
Cough was reported with use of TOBI Podhaler in clinical studies. Based on clinical trial data the inhalation powder TOBI Podhaler was associated with a higher reported rate of cough compared with tobramycin nebuliser solution (TOBI). Cough was not related to bronchospasm. Children below the age of 13 years may be more likely to cough when treated with TOBI Podhaler compared with older subjects.
If there is evidence of continued therapy-induced cough with TOBI Podhaler, the physician should consider whether an approved tobramycin nebuliser solution should be used as an alternative treatment. Should cough remain unchanged, other antibiotics should be considered.
Haemoptysis
Haemoptysis is a complication in cystic fibrosis and is more frequent in adults. Patients with haemoptysis (>60 ml) were excluded from the clinical studies so no data exist on the use of TOBI Podhaler in these patients. This should be taken into account before prescribing TOBI Podhaler, considering the inhalation powder TOBI Podhaler was associated with a higher rate of cough (see above). The use of TOBI Podhaler in patients with clinically significant haemoptysis should be undertaken or continued only if the benefits of treatment are considered to outweigh the risks of inducing further haemorrhage.
Other precautions
Patients receiving concomitant parenteral aminoglycoside therapy (or any medication affecting renal excretion, such as diuretics) should be monitored as clinically appropriate taking into account the risk of cumulative toxicity. This includes monitoring of serum concentrations of tobramycin. In patients with a predisposing risk due to previous prolonged, systemic aminoglycoside therapy it may be necessary to consider renal and audiological assessment before initiating TOBI Podhaler therapy.
See also “Monitoring of serum tobramycin concentrations” above.
Caution should be exercised when prescribing TOBI Podhaler to patients with known or suspected neuromuscular disorders such as myasthenia gravis or Parkinson’s disease.
Aminoglycosides may aggravate muscle weakness because of a potential curare-like effect on neuromuscular function.
The development of antibiotic-resistant P. aeruginosa and superinfection with other pathogens represent potential risks associated with antibiotic therapy. In clinical studies, some patients on TOBI Podhaler therapy showed an increase in aminoglycoside minimum inhibitory concentrations (MIC) for P. aeruginosa isolates tested. MIC increases observed were in large part reversible during off treatment periods.
There is a theoretical risk that patients being treated with TOBI Podhaler may develop P.
aeruginosa isolates resistant to intravenous tobramycin over time (see section 5.1). Development of resistance during inhaled tobramycin therapy could limit treatment options during acute exacerbations; this should be monitored.

Data in different age groups
In a 6-month (3 treatment cycles) study of TOBI Podhaler versus tobramycin nebuliser solution, which included a majority of tobramycin-experienced adult patients with chronic pulmonary P.
aeruginosa infection, the suppression of sputum P. aeruginosa density was similar across age groups in both arms; however the increase from baseline FEV1 was larger in younger age groups (6 - <20) than in the adult subgroup (20 years and older) in both arms. See also section 5.1 for the profile of response of TOBI Podhaler compared to tobramycin nebuliser solution. Adult patients tended to discontinue more frequently for tolerability reasons with TOBI Podhaler than with the nebuliser solution. See also section 4.8.
If clinical deterioration of pulmonary status is evident, additional or alternative anti-pseudomonal therapy should be considered.
Observed benefits on lung function and P. aeruginosa suppression should be assessed in the context of the patient’s tolerance of TOBI Podhaler.
Safety and efficacy have not been studied in patients with forced expiratory volume in 1 second (FEV1) <25% or >80% predicted, or patients colonised with Burkholderia cepacia.

Effects on Driving

4.7    Effects on ability to drive and use machines

TOBI Podhaler has no or negligible influence on the ability to drive and use machines.