Tobi Podhaler · 4.1 Therapeutic indications · 1

HOS-095904 · has-adverse-reaction-information · PDF-Seite 7

Summary of the safety profile The most commonly reported adverse reactions in the main safety, active-controlled clinical study with TOBI Podhaler versus tobramycin nebuliser solution in cystic fibrosis patients with P. aeruginosa infection were cough, productive cough, pyrexia, dyspnoea, oropharyngeal pain, dysphonia and haemoptysis. In the placebo-controlled study with TOBI Podhaler, the adverse reactions for which reported frequency was higher with TOBI Podhaler than with placebo were pharyngolaryngeal pain, dysgeusia and dysphonia. The vast majority of adverse reactions reported with TOBI Podhaler were mild or moderate, and severity did not appear to differ between cycles or between the entire study and on-treatment periods. Tabulated summary of adverse reactions Adverse drug reactions in Table 1 are listed according to system organ classes in MedDRA. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). The frequencies in Table 1 are based on the reporting rates from the active-controlled study. Table 1 Adverse reactions Adverse reactions Frequency category Ear and labyrinth disorders Hearing loss Common Tinnitus Common Vascular disorders Haemoptysis Very common Epistaxis Common Respiratory, thoracic and mediastinal disorders Dyspnoea Very common Dysphonia Very common Productive cough Very common Cough Very common Wheezing

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HOS-095900 · has-contraindication-information · PDF-Seite 3

Hypersensitivity to the active substance and any aminoglycoside, or to any of the excipients listed in section 6.1.

HOS-095899 · has-indication-information · PDF-Seite 2

TOBI Podhaler is indicated for the suppressive therapy of chronic pulmonary infection due to Pseudomonas aeruginosa in adults and children aged 6 years and older with cystic fibrosis. See sections 4.4 and 5.1 regarding data in different age groups. Consideration should be given to official guidance on the appropriate use of antibacterial agents.

HOS-095902 · has-interaction-information · PDF-Seite 6

No interaction studies have been performed with TOBI Podhaler. Based on the interaction profile for tobramycin following intravenous and aerosolised administration, concurrent and/or sequential use of TOBI Podhaler is not recommended with other medicinal products with nephrotoxic or ototoxic potential. Concomitant use of TOBI Podhaler with diuretic compounds (such as ethacrynic acid, furosemide, urea or intravenous mannitol) is not recommended. Such compounds can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. See also information on previous and concomitant use of systemic aminoglycosides and diuretics in section 4.4. Other medicinal products that have been reported to increase the potential toxicity of parenterally administered aminoglycosides include: - amphotericin B, cefalotin, ciclosporin, tacrolimus, polymyxins (risk of increased nephrotoxicity); - platinum compounds (risk of increased nephrotoxicity and ototoxicity); - anticholinesterases, botulinum toxin (neuromuscular effects). In clinical studies, patients receiving TOBI Podhaler continued to take dornase alfa, bronchodilators, inhaled corticosteroids and macrolides, no evidence of drug interactions with these medicines was identified.

HOS-095903 · has-pregnancy-information · PDF-Seite 6

Pregnancy There are no adequate data on the use of tobramycin via inhalation in pregnant women. Animal studies with tobramycin do not indicate a teratogenic effect (see section 5.3). However, aminoglycosides can cause foetal harm (e.g. congenital deafness) when high systemic concentrations are achieved in a pregnant woman. Systemic exposure following inhalation of TOBI Podhaler is very low, however TOBI Podhaler should not be used during pregnancy unless clearly necessary, i.e. when the benefits to the mother outweigh the risks to the foetus. Patients who use TOBI Podhaler during pregnancy, or become pregnant while taking TOBI Podhaler, should be informed of the potential hazard to the foetus. Breast-feeding Tobramycin is excreted in human breast milk after systemic administration. The amount of tobramycin excreted in human breast milk after administration by inhalation is not known, though it is estimated to be very low considering the low systemic exposure. Because of the potential for ototoxicity and nephrotoxicity in infants, a decision should be made whether to terminate breast-feeding or discontinue treatment with TOBI Podhaler, taking into account the importance of the treatment to the mother. Fertility No effect on male or female fertility was observed in animal studies after subcutaneous administration (see section 5.3). 6

HOS-095901 · has-warning-information · PDF-Seite 3

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. 3 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, however acute kidney injury (AKI) has been reported post-marketing with the use of inhaled tobramycin (see section 4.8). 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

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