Tobi Podhaler

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ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 
TOBI Podhaler 28 mg inhalation powder, hard capsules 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each hard capsule contains 28 mg tobramycin. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Inhalation powder, hard capsule 
 
Clear colourless capsules containing a white to almost white powder, with “NVR AVCI” printed in 
blue on one part of the capsule and Novartis logo printed in blue on the other part of the capsule. 
 
 
4. CLINICAL PARTICULARS 
 
4.1 Therapeutic indications 
 
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. 
 
4.2 Posology and method of administration 
 
Posology 
 
The dose of TOBI Podhaler is the same for all patients within the approved age range, regardless of 
age or weight. The recommended dose is 112 mg tobramycin (4 x 28 mg capsules), administered twice 
daily for 28 days. TOBI Podhaler is taken in alternating cycles of 28 days on treatment followed by 
28 days off treatment. The two doses (of 4 capsules each) should be inhaled as close as possible to 
12 hours apart and not less than 6 hours apart. 
 
Missed doses 
In case of missed dose with at least 6 hours until the next dose, the patient should take the dose as soon 
as possible. Otherwise, the patient should wait for the next dose and not inhale more capsules to make 
up for the missed dose. 
 
Duration of treatment 
Treatment with TOBI Podhaler should be continued on a cyclical basis for as long as the physician 
considers the patient is gaining clinical benefit from the treatment with TOBI Podhaler. If clinical 
deterioration of pulmonary status is evident, additional or alternative anti-pseudomonal therapy should 
be considered. See also information on clinical benefit and tolerability in sections 4.4, 4.8 and 5.1. 
 
Special populations 
 
Elderly patients (≥65 years) 
There are insufficient data in this population to support a recommendation for or against dose 
adjustment. 



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Renal impairment 
Tobramycin is primarily excreted unchanged in the urine and renal function is expected to affect the 
exposure to tobramycin. Patients with serum creatinine 2 mg/dl or more and blood urea nitrogen 
(BUN) 40 mg/dl or more have not been included in clinical studies and there are no data in this 
population to support a recommendation for or against dose adjustment with TOBI Podhaler. Caution 
should be exercised when prescribing TOBI Podhaler to patients with known or suspected renal 
dysfunction. 
 
Please also refer to nephrotoxicity information in section 4.4. 
 
Hepatic impairment 
No studies have been performed on patients with hepatic impairment. As tobramycin is not 
metabolised, an effect of hepatic impairment on the exposure to tobramycin is not expected. 
 
Patients after organ transplantation 
Adequate data do not exist for the use of TOBI Podhaler in patients after organ transplantation. No 
recommendation for or against dose adjustment can be made for patients after organ transplantation. 
 
Paediatric patients 
The safety and efficacy of TOBI Podhaler in children aged under 6 years have not been established. 
No data are available. 
 
Method of administration 
 
Inhalation use. 
 
TOBI Podhaler is administered by inhalation using the Podhaler device (see section 6.6 for detailed 
instructions for use). It must not be administered by any other route or using any other inhaler. 
 
Caregivers should provide assistance to children starting TOBI Podhaler treatment, particularly those 
aged 10 years or younger, and should continue to supervise them until they are able to use the 
Podhaler device properly without help. 
 
TOBI Podhaler capsules must not be swallowed. Each TOBI Podhaler capsule should be inhaled with 
two breath-hold manoeuvres and checked to ensure it is empty. 
 
Where patients are receiving several different inhaled medicinal products and chest physiotherapy, it is 
recommended that TOBI Podhaler is taken last. 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance and any aminoglycoside, or to any of the excipients listed in 
section 6.1. 
 
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. 



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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. 
 
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. 
 



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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 >75% predicted, or patients colonised with Burkholderia cepacia. 
 



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4.5 Interaction with other medicinal products and other forms of interaction 
 
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 coumpounds 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. 
 
4.6 Fertility, pregnancy and lactation 
 
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). 
 
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. 
 



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4.8 Undesirable effects 
 
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 using the following 
convention (CIOMS III) is also provided for each adverse drug reaction: 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: frequency 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 Common 
Rales Common 
Chest discomfort Common 
Nasal congestion Common 
Bronchospasm Common 
Aphonia Common 
Sputum discoloured Not known 



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Gastrointestinal disorders 
Oropharnygeal pain Very common 
Vomiting Common 
Diarrhoea Common 
Throat irritation Common 
Nausea Common 
Dysgeusia Common 
Skin and subcutaneous tissue disorders 
Rash Common 
Musculoskeletal, connective tissue and bone disorders  
Musculoskeletal chest pain Common 
General disorders and administration site conditions  
Pyrexia Very common 
Malaise Not known 

 
Description of selected adverse drug reactions 
 
Cough was the most frequently reported adverse reaction in both clinical studies. However, no 
association was observed in either clinical study between the incidence of bronchospasm and cough 
events. 
 
In the active-controlled study, audiology testing was performed in selected centres accounting for 
about a quarter of the study population. Four patients in the TOBI Podhaler treatment group 
experienced significant decreases in hearing which were transient in three patients and persistent in 
one case. 
 
In the active-controlled open-label study, patients aged 20 years and older tended to discontinue more 
frequently with TOBI Podhaler than with the nebuliser solution; discontinuations due to adverse 
events accounted for about half of the discontinuations with each formulation. In children under 
13 years of age, discontinuations were more frequent in the TOBI nebuliser solution arm whereas in 
patients aged 13 to 19, discontinuation rates with both formulations were similar. 
 
Reporting of suspected adverse reactions 
 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
4.9 Overdose 
 
Adverse reactions specifically associated with overdose of TOBI Podhaler have not been identified. 
The maximum tolerated daily dose of TOBI Podhaler has not been established. Tobramycin serum 
concentrations may be helpful in monitoring overdosage. In case of signs of acute toxicity, immediate 
withdrawal of TOBI Podhaler and testing of renal function are recommended. In the event of 
accidental oral ingestion of TOBI Podhaler capsules, toxicity is unlikely as tobramycin is poorly 
absorbed from an intact gastrointestinal tract. Haemodialysis may be helpful in removing tobramycin 
from the body. 
 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


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5. PHARMACOLOGICAL PROPERTIES 
 
5.1 Pharmacodynamic properties 
 
Pharmacotherapeutic group: Antibacterials for systemic use, Aminoglycoside antibacterials, ATC 
Code: J01GB01 
 
Mechanism of action 
 
Tobramycin is an aminoglycoside antibiotic produced by Streptomyces tenebrarius. It acts primarily 
by disrupting protein synthesis leading to altered cell membrane permeability, progressive disruption 
of the cell envelope and eventual cell death. It is bactericidal at concentrations equal to or slightly 
greater than inhibitory concentrations. 
 
Breakpoints 
 
Established susceptibility breakpoints for parenteral administration of tobramycin are inappropriate in 
the aerosolised administration of the medicinal product. 
 
Sputum from cystic fibrosis exhibits an inhibitory action on the local biological activity of inhaled 
aminoglycosides. This necessitates sputum concentrations of tobramycin after inhalation to be about 
ten-fold above the minimum inhibitory concentration (MIC) or higher for P. aeruginosa suppression. 
In the active-controlled study, at least 89% of patients had P. aeruginosa isolates with MICs at least 
15 times lower than mean post-dose sputum concentration, both at baseline and at the end of the third 
active treatment cycle. 
 
Susceptibility 
 
In the absence of conventional susceptibility breakpoints for the inhaled route of administration, 
caution must be exercised in defining organisms as susceptible or insusceptible to inhaled tobramycin. 
 
The clinical significance of changes in MICs of tobramycin for P. aeruginosa has not been clearly 
established in the treatment of cystic fibrosis patients. Clinical studies with inhaled tobramycin 
solution (TOBI) have shown a small increase in tobramycin, amikacin and gentamicin Minimum 
Inhibitory Concentrations for P. aeruginosa isolates tested. In the open label extensions, each 
additional 6 months of treatment resulted in incremental increases similar in magnitude to that 
observed in the 6 months of placebo-controlled studies. 
 
Resistance to tobramycin involves different mechanisms. The main resistance mechanisms are drug 
efflux and drug inactivation by modifying enzymes. The unique characteristics of chronic P. 
aeruginosa infections in CF patients, such as anaerobic conditions and high frequency of genetic 
mutations, may also be important factors for reduced susceptibility of P. aeruginosa in CF patients. 
 
Based upon in vitro data and/or clinical trial experience, the organisms associated with pulmonary 
infections in CF may be expected to respond to TOBI Podhaler therapy as follows: 
 

Susceptible Pseudomonas aeruginosa 
Haemophilus influenzae 
Staphylococcus aureus 

Insusceptible Burkholderia cepacia 
Stenotrophomonas maltophilia 
Alcaligenes xylosoxidans 

 
Clinical experience 
 
The TOBI Podhaler Phase III clinical development programme consisted of two studies and 
612 treated patients with a clinical diagnosis of CF, confirmed by quantitative pilocarpine 



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iontophoresis sweat chloride test or well-characterised disease causing mutations in each cystic 
fibrosis transmembrane regulator (CFTR) gene, or abnormal nasal transepithelial potential difference 
characteristic of CF. 
 
In the placebo controlled study, patients were aged 6 - ≤22 years with an FEV1 at screening of between 
25% and 84% of predicted normal values for their age, sex and height based upon Knudson criteria. In 
the active controlled studies, all patients were aged >6years old (range 6-66 years) with an FEV1 % 
predicted at screening of between 24% and 76%. In addition, all patients were infected with P. 
aeruginosa as demonstrated by a positive sputum or throat culture (or bronchoalveolar lavage) within 
6 months prior to screening, and also in a sputum culture taken at the screening visit. 
 
In a randomised, double-blind, placebo-controlled, multicentre study, TOBI Podhaler 112 mg (4 x 
28 mg capsules) was administered twice daily, for three cycles of 28 days on-treatment and 28 days 
off-treatment (a total treatment period of 24 weeks). Patients who were randomised to the placebo 
treatment group received placebo during the first treatment cycle and TOBI Podhaler in the subsequent 
two cycles. Patients in this study had no exposure to inhaled tobramycin for at least 4 months prior to 
study start. 
 
TOBI Podhaler significantly improved lung function compared with placebo, as shown by the relative 
increase in percent predicted FEV1 of about 13% after 28 days of treatment. The improvements in lung 
function achieved during the first treatment cycle were maintained during the two subsequent cycles of 
treatment with TOBI Podhaler. 
 
When patients in the placebo treatment group were switched from placebo to TOBI Podhaler at the 
start of the second treatment cycle, they experienced a similar improvement from baseline in percent 
predicted FEV1. Treatment with TOBI Podhaler for 28 days resulted in a statistically significant 
reduction in P. aeruginosa sputum density (mean difference with placebo about 2.70 log10 in colony 
forming units/CFUs). 
 
In a second open-label, multicentre study, patients received treatment with either TOBI Podhaler 
(112 mg) or tobramycin 300 mg/5 ml nebuliser solution (TOBI), administered twice daily for three 
cycles. A majority of the patients were tobramycin-experienced adults with chronic pulmonary P. 
aeruginosa infection. 
 
Treatment with both TOBI Podhaler and tobramycin 300 mg/5 ml nebuliser solution (TOBI) resulted 
in relative increases from baseline to day 28 of the third treatment cycle in percent predicted FEV1 of 
5.8% and 4.7%, respectively. The improvement in percent predicted FEV1 was numerically greater in 
the TOBI Podhaler treatment group and was statistically non-inferior to TOBI nebuliser solution. 
Although the magnitude of improvements in lung function was smaller in this study, this is explained 
by the previous exposure of this patient population to treatment with inhaled tobramycin. Over half of 
the patients in both the TOBI Podhaler and TOBI nebuliser solution treatment groups received new 
(additional) anti-pseudomonal antibiotics (64.9% and 54.5% respectively, the difference consisting 
mainly of oral ciprofloxacin use). The proportions of patients requiring hospitalisation for respiratory 
events were 24.4% with TOBI Podhaler and 22.0% with TOBI nebuliser solution. 
 
A difference in FEV1 response by age was noted. In the patients aged <20 years the increase from 
baseline percent predicted FEV1 was larger: 11.3% for TOBI Podhaler and 6.9% for the nebuliser 
solution after 3 cycles. A numerically lower response in patients aged ≥20 years was observed: the 
change from baseline FEV1 observed in the patients aged ≥20 years was smaller (0.3% with TOBI 
Podhaler and 0.9% with TOBI nebuliser solution). 
 
Furthermore, an improvement of 6% in percent predicted FEV1 was obtained in about 30% versus 
36% of the adult patients in the TOBI Podhaler and TOBI nebuliser solution group respectively. 
 
Treatment with TOBI Podhaler for 28 days resulted in a statistically significant reduction in P. 
aeruginosa sputum density (-1.61 log10 CFUs), as did the nebuliser solution (-0.77 log10 CFUs). 
Suppression of sputum P. aeruginosa density was similar across age groups in both arms. In both 



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studies, there was a trend for a recovery of P. aeruginosa density after the 28 days off-treatment 
period, which was reversed after a further 28 days on-treatment. 
 
In the active-controlled study, administration of a TOBI Podhaler dose was faster with a mean 
difference of approximately 14 minutes (6 minutes vs. 20 minutes with the nebuliser solution). Patient-
reported convenience and overall treatment satisfaction (as collected through a patient-reported 
outcomes questionnaire) were consistently higher with TOBI Podhaler compared with tobramycin 
nebuliser solution in each cycle. 
 
For safety results see section 4.8 
 
Paediatric population 
 
The European Medicines Agency has waived the obligation to submit the results of studies with TOBI 
Podhaler in one or more subsets of the paediatric population in treatment of pseudomonas aeruginosa 
pulmonary infection/colonisation in patients with cystic fibrosis (see section 4.2 for information on 
paediatric use). 
 
5.2 Pharmacokinetic properties 
 
Absorption 
 
The systemic exposure to tobramycin after inhalation of TOBI Podhaler is expected to be primarily 
from the inhaled portion of the medicinal product as tobramycin is not absorbed to any appreciable 
extent when administered via the oral route. 
 
Serum concentrations 
After inhalation of a 112 mg single dose (4 x 28 mg capsules) of TOBI Podhaler in cystic fibrosis 
patients, the maximum serum concentration (Cmax) of tobramycin was 1.02 ± 0.53 μg/ml (mean ± SD) 
and the median time to reach the peak concentration (Tmax) was one hour. In comparison, after 
inhalation of a single dose of tobramycin 300 mg/5 ml nebuliser solution (TOBI), Cmax was 
1.04 ± 0.58 µg/ml and median Tmax was one hour. The extent of systemic exposure (AUC) was also 
similar for the 112 mg TOBI Podhaler dose and the 300 mg tobramycin nebuliser solution dose. At the 
end of a 4-week dosing cycle of TOBI Podhaler (112 mg twice daily), maximum serum concentration 
of tobramycin 1 hour after dosing was 1.99 ± 0.59 µg/ml. 
 
Sputum concentrations 
After inhalation of a 112 mg single dose (4 x 28 mg capsules) of TOBI Podhaler in cystic fibrosis 
patients, sputum Cmax of tobramycin was 1047 ± 1080 µg/g (mean ± SD). In comparison, after 
inhalation of a single 300 mg dose of tobramycin nebuliser solution (TOBI), sputum Cmax was 
737.3 ± 1028.4 µg/g. The variability in pharmacokinetic parameters was higher in sputum as 
compared to serum. 
 
Distribution 
 
A population pharmacokinetic analysis for TOBI Podhaler in cystic fibrosis patients estimated the 
apparent volume of distribution of tobramycin in the central compartment to be 84.1 litres for a typical 
CF patient. While the volume was shown to vary with body mass index (BMI) and lung function (as 
FEV1% predicted), model-based simulations showed that peak (Cmax) and trough (Ctrough) 
concentrations were not impacted markedly with changes in BMI or lung function. 
 
Biotransformation 
 
Tobramycin is not metabolised and is primarily excreted unchanged in the urine. 
 



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Elimination 
 
Tobramycin is eliminated from the systemic circulation primarily by glomerular filtration of the 
unchanged compound. The apparent terminal half-life of tobramycin in serum after inhalation of a 
112 mg single dose of TOBI Podhaler was approximately 3 hours in cystic fibrosis patients and 
consistent with the half-life of tobramycin after inhalation of tobramycin 300 mg/5 ml nebuliser 
solution (TOBI). 
 
A population pharmacokinetic analysis for TOBI Podhaler in cystic fibrosis patients aged 6 to 66 years 
estimated the apparent serum clearance of tobramycin to be 14 litres/h. This analysis did not show 
gender or age-related pharmacokinetic differences 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal that the main hazard for humans, based on studies of safety pharmacology, 
repeated dose toxicity, genotoxicity, or toxicity to reproduction, consists of renal toxicity and 
ototoxicity. In general, toxicity is seen at higher systemic tobramycin levels than are achievable by 
inhalation at the recommended clinical dose. 
 
Carcinogenicity studies with inhaled tobramycin do not increase the incidence of any variety of 
tumour. Tobramycin showed no genotoxic potential in a battery of genotoxicity tests. 
 
No reproduction toxicology studies have been conducted with tobramycin administered by inhalation. 
However, subcutaneous administration of tobramycin during organogenesis was not teratogenic nor 
embryotoxic. Severely maternally toxic doses to female rabbits (i.e. nephrotoxicity) lead to 
spontaneous abortions and death. Based on available data from animals a risk of toxicity (e.g. 
ototoxicity) at prenatal exposure levels cannot be excluded. 
 
Subcutaneous administration of tobramycin did not affect mating behaviour or cause impairment of 
fertility in male or female rats. 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Capsule content 
 
1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) 
Calcium chloride 
Sulfuric acid (for pH adjustment) 
 
6.2 Incompatibilities 
 
Not applicable 
 
6.3 Shelf life 
 
3 years 
 
Discard the Podhaler device and its case 1 week after first use. 
 
6.4 Special precautions for storage 
 
TOBI Podhaler capsules must always be stored in the blister to protect from moisture and only 
removed immediately before use. 
 



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6.5 Nature and contents of container 
 
The hard capsules are supplied in PVC/PA/Alu/PVC- PET/Alu blisters. 
 
The Podhaler inhalation device and its storage case are made from plastic materials (polypropylene). 
 
TOBI Podhaler is supplied in monthly packs containing 4 weekly cartons and a reserve Podhaler 
device in its storage case. Each weekly carton contains 56 x 28 mg capsules (7 blisters with 8 capsules 
per blister), and a Podhaler device in its storage case. 
 
Pack sizes 
 
56 capsules and 1 inhaler 
224 (4 x 56) capsules and 5 inhalers (monthly multipack) 
448 (8 x 56) capsules and 10 inhalers (2 x monthly multipack wrapped in foil) 
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal and other handling 
 
Only TOBI Podhaler capsules are to be used in the Podhaler device. No other inhaler may be used. 
TOBI Podhaler capsules must always be stored in the blister (capsule card), and only removed 
immediately before use. Each Podhaler device and its case are used for seven days and then discarded 
and replaced. Store the Podhaler device in its tightly closed case when not in use. 
 
Basic instructions for use are given below, more detailed instructions are available from the patient 
leaflet. 
 
1. Wash and fully dry hands. 
2. Just before use, remove the Podhaler device from its case. Briefly inspect the inhaler to make 

sure it is not damaged or dirty. 
3. Holding the body of the inhaler, unscrew and remove the mouthpiece from the inhaler body. Set 

the mouthpiece aside on a clean, dry surface. 
4. Separate the morning and evening doses from the capsule card. 
5. Peel back the foil from the capsule card to reveal one TOBI Podhaler capsule and remove it 

from the card. 
6. Immediately insert the capsule into the inhaler chamber. Replace the mouthpiece and screw it 

on firmly until it stops. Do not overtighten. 
7. To puncture capsule, hold the inhaler with the mouthpiece down, press the button firmly with 

your thumb as far as it will go, then release the button. 
8. Fully exhale away from the inhaler. 
9. Place mouth over the mouthpiece creating a tight seal. Inhale the powder deeply with a single 

continuous inhalation. 
10. Remove inhaler from mouth, and hold breath for approximately 5 seconds, then exhale normally 

away from the inhaler. 
11. After a few normal breaths away from the inhaler, perform a second inhalation from the same 

capsule. 
12. Unscrew mouthpiece and remove the capsule from the chamber. 
13. Inspect the used capsule. It should appear punctured and empty. 

• If the capsule is punctured but still contains some powder, place it back into the inhaler 
and take another two inhalations from the capsule. Reinspect capsule. 

• If the capsule appears to be unpunctured, place it back into the inhaler, press the button 
firmly as far as it goes and take another two inhalations from the capsule. After this if the 
capsule is still full and appears to be unpunctured, replace the inhaler with the reserve 
inhaler and try again. 

14. Discard the empty capsule. 
15. Repeat, starting at step 5, for the remaining three capsules of the dose. 



14 

16. Replace the mouthpiece and screw it on firmly until it stops. When the full dose (4 capsules) has 
been inhaled, wipe mouthpiece with a clean dry cloth. 

17. Place inhaler back in storage case and close tightly. The inhaler should never be washed with 
water. 

 
See also section 4.2. 
 
Any unused product or waste material should be disposed of in accordance with local requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Mylan IRE Healthcare Limited 
Unit 35/36 Grange Parade,  
Baldoyle Industrial Estate, Dublin 13 
Ireland 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/652/001-003 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 20 July 2011 
Date of latest renewal: 18 February 2016 
 
 
10. DATE OF REVISION OF THE TEXT 
 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu 
 

http://www.ema.europa.eu/


15 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION 

 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
 



16 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturer responsible for batch release 
 
Novartis Pharma GmbH 
Roonstrasse 25 
D-90429 Nuremberg 
Germany 
 
McDermott Laboratories Ltd T/A Mylan Dublin Respiratory 
Unit 25, Baldoyle Industrial Estate 
Grange Road, Baldoyle  
Dublin 13, D13 N5X2 
Ireland 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to medical prescription. 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 
 
• Periodic Safety Update Reports 
 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
• Risk Management plan (RMP) 
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP. 
 
An updated RMP should be submitted: 
• At the request of the European Medicines Agency; 
• Whenever the risk management system is modified, especially as the result of new information 

being received that may lead to significant change to the benefit/risk profile or as the result of 
an important (pharmacovigilance or risk minimisation) milestone being reached. 

 



17 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



18 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



19 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON OF UNIT PACK (INCLUDING BLUE BOX) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
TOBI Podhaler 28 mg inhalation powder, hard capsules 
tobramycin 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 28 mg tobramycin. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), calcium chloride and sulphuric acid 
(for pH adjustment). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Inhalation powder, hard capsules 
 
56 capsules + 1 inhaler 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Inhalation use 
Read the package leaflet before use. 
For use only with the inhaler provided in the pack. 
Always store inhaler in its case. 
Do not swallow capsules. 
4 capsules = 1 dose 
Lift here to open. 
 
(To be displayed only on the inner lid of the outer carton of unit pack) 
Read the package leaflet before use. 
4 capsules = 1 dose 
Do not push the capsules through the foil. 
Tear the perforations along the length then width: see Figures (a) and (b). 
Then peel back the foil by rolling it back from the capsule card to reveal one capsule at a time, see 
Figures (c) and (d). Hold the foil close to where you are rolling back. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 



20 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package in order to protect from moisture and only remove immediately before 
use. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Mylan IRE Healthcare Limited 
Unit 35/36 Grange Parade,  
Baldoyle Industrial Estate, Dublin 13 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/652/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
TOBI Podhaler 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 



21 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 



22 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
WEEKLY INTERMEDIATE CARTON OF MULTIPACK (WITHOUT BLUE BOX) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
TOBI Podhaler 28 mg inhalation powder, hard capsules 
tobramycin 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 28 mg tobramycin. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), calcium chloride and sulphuric acid 
(for pH adjustment). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Inhalation powder, hard capsules 
 
56 capsules + 1 inhaler 
Component of a multipack. Not to be sold separately. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Inhalation use 
Read the package leaflet before use. 
For use only with the inhaler provided in the pack. 
Always store inhaler in its case. 
Do not swallow capsules. 
4 capsules = 1 dose 
Lift here to open. 
 
(To be displayed only on the inner lid of the intermediate carton of multipack) 
Read the package leaflet before use. 
4 capsules = 1 dose 
Do not push the capsules through the foil. 
Tear the perforations along the length then width: see Figures (a) and (b). 
Then peel back the foil by rolling it back from the capsule card to reveal one capsule at a time, see 
Figures (c) and (d). Hold the foil close to where you are rolling back. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 



23 

 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package in order to protect from moisture and only remove immediately before 
use. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Mylan IRE Healthcare Limited 
Unit 35/36 Grange Parade,  
Baldoyle Industrial Estate, Dublin 13 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/652/002 monthly multipack 
EU/1/10/652/003 2 x monthly multipack wrapped in foil 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
TOBI Podhaler 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 



24 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
 



25 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON OF MULTIPACK (INCLUDING BLUE BOX) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
TOBI Podhaler 28 mg inhalation powder, hard capsules 
tobramycin 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 28 mg tobramycin. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), calcium chloride and sulphuric acid 
(for pH adjustment). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Inhalation powder, hard capsules 
 
Multipack: 224 capsules (4 packs of 56 + 1 inhaler) + reserve inhaler 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Inhalation use 
Read the package leaflet before use. 
For use only with the inhaler provided in the pack. 
Always store inhaler in its case. 
Do not swallow capsules. 
Lift here to open. 
1 reserve inhaler inside. Use this if your weekly inhaler is not functioning correctly, is wet, or has 
dropped on the ground. 
 
(To be displayed only on the inner lid of the outer carton of multipack) 
Read the package leaflet before use. 
Do not use each inhaler and its case for longer than 1 week. 
Please discard inhaler and its case after 1 week of use. 
FOUR capsules are required for ONE complete dose. 
4 capsules = 1 dose 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 



26 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package in order to protect from moisture and only remove immediately before 
use. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Mylan IRE Healthcare Limited 
Unit 35/36 Grange Parade,  
Baldoyle Industrial Estate, Dublin 13 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/652/002 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
TOBI Podhaler 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 



27 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 
 



28 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
MONTHLY INTERMEDIATE CARTON OF MULTIPACK COMPRISING 2 MONTHLY 
PACKS, EACH CONTAINING 4 WEEKLY PACKS) (WITHOUT BLUE BOX) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
TOBI Podhaler 28 mg inhalation powder, hard capsules 
tobramycin 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 28 mg tobramycin. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), calcium chloride and sulphuric acid 
(for pH adjustment). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Inhalation powder, hard capsules 
 
224 capsules + 5 inhalers 
Monthly pack. Component of a multipack. Not to be sold separately. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Inhalation use 
Read the package leaflet before use. 
For use only with the inhaler provided in the pack. 
Always store inhaler in its case. 
Do not swallow capsules. 
Lift here to open. 
1 reserve inhaler inside. Use this if your weekly inhaler is not functioning correctly, is wet, or has 
dropped on the ground. 
 
(To be displayed only on the inner lid of the outer carton of multipack) 
Read the package leaflet before use. 
Do not use each inhaler and its case for longer than 1 week. 
Please discard inhaler and its case after 1 week of use. 
FOUR capsules are required for ONE complete dose. 
4 capsules = 1 dose 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 



29 

 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package in order to protect from moisture and only remove immediately before 
use. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Mylan IRE Healthcare Limited 
Unit 35/36 Grange Parade,  
Baldoyle Industrial Estate, Dublin 13 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/652/003 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
TOBI Podhaler 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 



30 

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
WRAPPER LABEL ON MULTIPACKS WRAPPED IN FOIL COMPRISING 2 MONTHLY 
PACKS, EACH CONTAINING 4 WEEKLY PACKS) (INCLUDING BLUE BOX) 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
TOBI Podhaler 28 mg inhalation powder, hard capsules 
tobramycin 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each hard capsule contains 28 mg tobramycin. 
 
 
3. LIST OF EXCIPIENTS 
 
Contains 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), calcium chloride and sulphuric acid 
(for pH adjustment). 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Inhalation powder, hard capsules 
 
Multipack: 448 capsules (2 packs of 224 + 5 inhalers) 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Inhalation use 
Read the package leaflet before use. 
For use only with the inhaler provided in the pack. 
Always store inhaler in its case. 
Do not swallow capsules. 
Lift here to open. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



31 

9. SPECIAL STORAGE CONDITIONS 
 
Store in the original package in order to protect from moisture and only remove immediately before 
use. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Mylan IRE Healthcare Limited 
Unit 35/36 Grange Parade,  
Baldoyle Industrial Estate, Dublin 13 
Ireland 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/10/652/003 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
TOBI Podhaler 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 
 
PC: 
SN: 
NN: 



32 

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTERS 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
TOBI Podhaler 28 mg inhalation powder, hard capsules 
tobramycin 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Mylan IRE Healthcare Limited 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
Inhalation use only. Do not swallow. 
Use capsule immediately after removal from blister. 
Do not push capsule through foil. 
4 capsules = 1 dose 



33 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 



34 

Package leaflet: Information for the user 
 

TOBI Podhaler 28 mg inhalation powder, hard capsules 
tobramycin 

 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
• Keep this leaflet. You may need to read it again. 
• If you have any further questions, ask your doctor or pharmacist. 
• This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
• If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
What is in this leaflet 
 
1. What TOBI Podhaler is and what it is used for 
2. What you need to know before you take TOBI Podhaler 
3. How to take TOBI Podhaler 
4. Possible side effects 
5. How to store TOBI Podhaler 
6. Contents of the pack and other information 
 Instructions for use with the Podhaler device (overleaf) 
 
 
1. What TOBI Podhaler is and what it is used for 
 
What TOBI Podhaler is 
TOBI Podhaler contains a medicine called tobramycin which is an antibiotic. This antibiotic belongs 
to a class called aminoglycosides. 
 
What TOBI Podhaler is used for 
TOBI Podhaler is used in patients aged 6 years and older who have cystic fibrosis to treat lung 
infections caused by bacteria called Pseudomonas aeruginosa. 
 
For the best results from this medicine, please use it as this leaflet instructs you. 
 
How TOBI Podhaler works 
TOBI Podhaler is a powder for inhalation that is filled into capsules. When you inhale TOBI Podhaler, 
the antibiotic can enter directly into your lungs to fight against the bacteria causing the infection and to 
improve your breathing. 
 
What is Pseudomonas aeruginosa 
It is a very common bacterium that infects the lungs of nearly everyone with cystic fibrosis at some 
time during their lives. Some people do not get this infection until later on in their lives, while others 
get it very young. It is one of the most damaging bacteria for people with cystic fibrosis. If the 
infection is not properly fought, it will continue to damage your lungs, causing further problems to 
your breathing. 
 
 
2. What you need to know before you take TOBI Podhaler 
 
Do not take TOBI Podhaler 
• if you are allergic to tobramycin, to any type of aminoglycoside antibiotic, or to any of the 

other ingredients of this medicine (listed in section 6). 
If this applies to you, tell your doctor without taking TOBI Podhaler. 
If you think you may be allergic, ask your doctor for advice. 



35 

 
Warnings and precautions 
Tell your doctor if you have ever had any of the following conditions: 
• hearing problems (including noises in the ears and dizziness) 
• kidney problems 
• unusual difficulty in breathing with wheezing or coughing, chest tightness 
• blood in your sputum (the substance you cough up) 
• muscle weakness that lasts or becomes worse over time, a symptom mostly related to conditions 

such as myasthenia or Parkinson’s disease. 
If any of these apply to you, tell your doctor before taking TOBI Podhaler. 
 
If you are aged 65 years or older, your doctor may perform additional tests to decide if TOBI Podhaler 
is right for you. 
 
Inhaling medicines can cause chest tightness and wheezing and this can happen immediately after 
inhalation of TOBI Podhaler. Your doctor will supervise your first dose of TOBI Podhaler and check 
your lung function before and after dosing. Your doctor may ask you to use other appropriate 
medicines before taking TOBI Podhaler. 
 
Inhaling medicines can also cause cough and this can happen with TOBI Podhaler. Talk to your doctor 
if the cough is persistent and is a burden for you. 
 
Strains of Pseudomonas can become resistant to treatment with an antibiotic over time. This means 
that TOBI Podhaler may not work as well as it should over time. Talk to your doctor if you are 
concerned about this. 
 
If you are taking tobramycin or another aminoglycoside antibiotic by injection, it can sometimes cause 
hearing loss, dizziness and kidney damage. 
 
Children 
TOBI Podhaler should not be given to children less than 6 years old. 
 
Other medicines and TOBI Podhaler 
Tell your doctor or a pharmacist if you are taking, have recently taken or might take any other 
medicines, including medicines obtained without a prescription. 
 
You should not take the following medicines while you are taking TOBI Podhaler: 
• Furosemide or ethacrynic acid, diuretics 
• Other medicines with diuretic properties such as urea or intravenous mannitol 
• Other medicines which may harm your kidneys or hearing. 
 
The following medicines can increase the chances of harmful effects occurring if they are given to you 
while you are also receiving injections of tobramycin or other aminoglycoside antibiotic: 
• Amphotericin B, cefalotin, polymyxins (used to treat microbial infections), ciclosporin, 

tacrolimus (used to reduce the activity of immune system). These medicines may harm the 
kidneys. 

• Platinum compounds such as carboplatin and cisplatin (used to treat some forms of cancer). 
These medicines may harm the kidneys or hearing. 

• Anticholinesterases such as neostigmine and pyridostigmine (used to treat muscle weakness), or 
botulinum toxin. These medicines may cause muscle weakness to appear or become worse.. 

 
If you are taking one or more of the above medicines, discuss with your doctor before you take TOBI 
Podhaler. 
 
Pregnancy and breast-feeding 
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask 



36 

your doctor or pharmacist for advice before using this medicine. 
 
It is not known whether inhaling this medicine when you are pregnant causes side effects. 
 
When they are given by an injection, tobramycin and other aminoglycoside antibiotics can cause harm 
to an unborn child, such as deafness. 
 
If you are breast feeding, you should talk to your doctor before taking this medicine. 
 
Driving and using machines 
TOBI Podhaler has no or negligible influence on the ability to drive and use machines. 
 
 
3. How to take TOBI Podhaler 
 
Always take TOBI Podhaler exactly as your doctor has told you. You should check with your doctor if 
you are not sure. 
 
Caregivers should provide assistance to children starting TOBI Podhaler treatment, particularly those 
aged 10 years or younger, and should continue to supervise them until they are able to use the 
Podhaler device properly without help. 
 
How much TOBI Podhaler to take 
Inhale the content of 4 capsules twice a day (4 capsules in the morning and 4 capsules in the evening), 
using the Podhaler device. 
The dose is the same for everyone aged 6 years and older. Do not exceed the recommended dose. 
 
When to take TOBI Podhaler 
Taking your capsules at the same time each day will help you remember when to take them. Inhale the 
content of 4 capsules twice a day as follows: 
• 4 capsules in the morning to be inhaled using the Podhaler device. 
• 4 capsules in the evening to be inhaled using the Podhaler device. 
• It is best to leave close to 12 hours between doses, but this must be at least 6 hours 
 
If you are taking several different inhaled treatments and following other therapies for cystic fibrosis, 
you should take TOBI Podhaler after all of these are done. Please check the order of medications with 
your doctor. 
 
How to take TOBI Podhaler 
• For inhalation use only. 
• Do not swallow the capsules 
• Only use the capsules with the inhaler provided in this pack. The capsules should remain in the 

capsule card until you need to use them. 
• When you start a new weekly pack of capsules, use the new inhaler that is supplied in the pack. 

Each inhaler is only used for 7 days. 
• Please read the instructions at the end of this leaflet for more information about how to use the 

inhaler. 
 
How long to take TOBI Podhaler 
After you have taken TOBI Podhaler for 28 days, you then have a 28-day break, during which you do 
not inhale any TOBI Podhaler. You then start another course. 
It is important that you keep using the product twice each day during your 28 days on treatment and 
that you keep to the 28-day on, 28-day off cycle. 



37 

 
 

ON TOBI Podhaler OFF TOBI Podhaler 
Take TOBI Podhaler 
twice a day, every day 
for 28 days 

Do not take any TOBI 
Podhaler for the next 
28 days 

 
 
   Repeat cycle 
 
Continue taking TOBI Podhaler as your doctor tells you. 
If you have questions about how long to take TOBI Podhaler for, talk to your doctor or your 
pharmacist. 
 
If you take more TOBI Podhaler than you should 
If you inhale too much TOBI Podhaler, tell your doctor as soon as possible. If TOBI Podhaler is 
swallowed, don’t worry but tell your doctor as soon as possible. 
 
If you forget to take TOBI Podhaler 
If you forget to take TOBI Podhaler and there are at least 6 hours to your next dose, take your dose as 
soon as you can. Otherwise, wait for your next dose. Do not take a double dose to make up for a 
forgotten dose. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
People with cystic fibrosis have many symptoms of the disease. These may still happen while taking 
TOBI Podhaler, but should not be any more frequent or seem worse than before. 
 
If your underlying lung disease seems worse while taking TOBI Podhaler, tell your doctor straight 
away. 
 
Some side effects can be serious 
• Unusual difficulty in breathing with wheezing or coughing and chest tightness (common). 
If you experience any of these, stop taking TOBI Podhaler and tell your doctor straight away. 
 
• Coughing up blood (very common) 
• Decreasing hearing (ringing in the ears is a potential warning sign of hearing loss), noises (such 

as hissing) in the ears (common). 
If you experience any of these, tell your doctor straight away. 
 
Other side effects may include: 
Very common (may affect more than 1 in 10 people) 
• Shortness of breath 
• Cough, productive cough, voice alteration (hoarseness) 
• Sore throat 
• Fever 
 
Common (may affect up to 1 in 10 people) 
• Wheezing, rales (crackles) 
• Chest discomfort, chest pain from muscles or skeletal origins 
• Blocked nose 



38 

• Nosebleed 
• Vomiting, nausea 
• Diarrhoea 
• Rash 
• Disturbed sense of taste. 
• Loss of voice 
 
Not known (frequency cannot be estimated from the available data) 
• Generally feeling unwell 
• Discoloration of the substance you cough up (sputum) 
 
Reporting of side effects 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. You can also report side effects directly via the national reporting system 
listed in Appendix V. By reporting side effects you can help provide more information on the safety of 
this medicine. 
 
 
5. How to store TOBI Podhaler 
 
• Keep this medicine out of the sight and reach of children. 
• Do not use this medicine after the expiry date which is stated on the box or capsule card. 
• Store in the original packaging in order to protect from moisture. 
 
Once removed from the capsule card (blister), a capsule should be used immediately. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
dispose of medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What TOBI Podhaler contains 
• The active substance is tobramycin. One capsule contains 28 mg tobramycin. 
• The other ingredients are DSPC (1,2-distearoyl-sn-glycero-3-phosphocholine), calcium 

chloride, sulfuric acid (for pH adjustment). 
 
What TOBI Podhaler looks like and contents of the pack 
TOBI Podhaler inhalation powder, hard capsules consist of a white to almost white powder for 
inhalation filled into clear colourless hard capsules with “NVR AVCI” imprinted in blue ink on one 
part of the capsule and the Novartis logo imprinted in blue on the other part of the capsule. 
 
TOBI Podhaler is supplied in monthly packs containing 4 weekly cartons and a reserve Podhaler 
device in its storage case. 
 
Each weekly carton contains 7 blisters (capsule cards) of 8 capsules each, and a Podhaler device in its 
storage case. 
 
The following pack sizes are available: 
56 inhalation powder, hard capsules and 1 inhaler (weekly pack) 
224 (4 x 56) inhalation powder, hard capsules and 5 inhalers (monthly multipack) 
448 (8 x 56) inhalation powder, hard capsules and 10 inhalers (2 x monthly multipack wrapped in foil) 
 
Not all pack sizes may be available in your country. 
 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


39 

Marketing Authorisation Holder 
Mylan IRE Healthcare Limited 
Unit 35/36 Grange Parade,  
Baldoyle Industrial Estate, Dublin 13 
Ireland 
 
Manufacturer 
Novartis Pharma GmbH 
Roonstrasse 25 
D-90429 Nuremberg 
Germany 
 
McDermott Laboratories Ltd T/A Mylan Dublin Respiratory 
Unit 25, Baldoyle Industrial Estate 
Grange Road, Baldoyle  
Dublin 13, D13 N5X2 
Ireland 
 
 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Mylan EPD bvba/sprl 
Tél/Tel: +32 2 658 61 00 
 

Lietuva 
BGP Products UAB 
Tel: +370 5 205 1288 
 

България 
Майлан ЕООД 
Тел: +359 2 44 55 400 
 

Luxembourg/Luxemburg 
Mylan EPD bvba/sprl 
Tél/Tel: +32 2 658 61 00 
 

Česká republika 
BGP Products s.r.o. 
Tel: +420 222 004 400 
 

Magyarország 
Mylan EPD Kft. 
Tel: +36 1 465 2100 
 

Danmark 
Mylan Denmark ApS 
Tlf: +45 28 11 69 32 
 

Malta 
VJ Salomone Pharma  
Tel: +356 21 22 01 74 
 

Deutschland 
Mylan Healthcare GmbH 
Tel: +49 6172 888 01 
 

Nederland 
Mylan Healthcare B.V. 
Tel: +31 20 426 3300 
 

Eesti 
BGP Products Switzerland GmbH Eesti filiaal 
Tel: + 372 6363 052 
  

Norge 
Mylan Healthcare Norge AS 
Tlf: +47 66 75 33 00 
 

Ελλάδα 
BGP ΠΡΟΪΟΝΤΑ Μ.Ε.Π.Ε. 
Τηλ: +30 210 9891 777 
 

Österreich 
Mylan Österreich GmbH 
Tel: + 43 1 86 390  
 

España 
Mylan Pharmaceuticals, S.L. 
Tel: +34 900 102 712 
 

Polska 
Mylan Healthcare Sp. z o.o. 
Tel: +48 22 546 6400 
 

France 
Mylan Medical SAS 

Portugal 
BGP Products, Unipessoal, Lda. 



40 

Tél: +33 1 56 64 10 70 
 

Tel: + 351 21 412 72 56 
 

Hrvatska 
Mylan Hrvatska d.o.o. 
Tel: +385 1 235 059 90 
 

România 
BGP PRODUCTS SRL 
Tel.: +40 372 579 000 
 

Ireland 
Mylan Ireland Limited 
Tel: +353 87 1694982 
 

Slovenija 
Mylan Healthcare d.o.o. 
Tel: +386 1 23 63 180 
 

Ísland 
Icepharma hf. 
Sími: + 354 540 8000 
 

Slovenská republika 
BGP Product s. r.o. 
Tel: +421 2 32 199 100 
 

Italia 
Mylan Italia SRL 
Tel: +39 0261246921 
 

Suomi/Finland 
Mylan Finland Oy 
Puh/Tel: +358 20 720 9555 
 

Κύπρος 
Bαρνάβας Χατζηπαναγής Λτδ 
Τηλ.: +357 22 207 700 
 

Sverige 
BGP Products AB  
Tel: +46 8 555 227 07 
 

Latvija 
BGP Products SIA 
Tālr:  +371 676 055 80 
 

United Kingdom 
Mylan Products Ltd. 
Tel: +44 1707 853000 

 
This leaflet was last revised in 
 
Other sources of information 
 
Detailed information on this medicine is available on the European Medicines Agency web site: 
http://www.ema.europa.eu 
 

http://www.ema.europa.eu/


41 

INSTRUCTIONS FOR USE OF THE PODHALER DEVICE 
 
Please read the following instructions carefully to learn how to use and care for your Podhaler device. 
 
Inside your TOBI Podhaler weekly pack 
Each weekly carton of TOBI Podhaler contains: 
• 1 inhaler (the Podhaler device) and its storage case. 
• 7 capsule cards (one card for each day of the week). 
• Each capsule card contains 8 capsules (corresponding to a daily dose: content of 4 capsules to 

be inhaled in the morning and content of 4 capsules to be inhaled in the evening). 
 
 

 
 

  
Capsule card Inhaler Storage case 
 
How to inhale your medicine with the Podhaler device 
• Only use Podhaler device contained in this pack. Do not use TOBI Podhaler capsules with 

any other device, and do not use the Podhaler device to take any other medicine. 
• When you start a new weekly pack of capsules, use the new Podhaler device that is supplied in 

the pack. Each Podhaler device is only used for 7 days. Ask your pharmacist how to dispose of 
medicines and inhalers no longer required. 

• Do not swallow the capsules. The powder in the capsules is for you to inhale. 
• Always keep the capsules in the capsule card until when you need to use them. Do not take the 

capsules out of the card in advance. 
• Store the Podhaler device in its tightly closed case when not in use. 
 

 

1. Wash and fully dry your hands. 
 

 

2. • Just before use, remove the inhaler from its case by 
holding the base and twisting off the top of the case in an 
anti-clockwise direction. 
• Set the top of the case aside. 
• Look at the inhaler to make sure it is not damaged or 
dirty. 
• Stand the inhaler upright in the base of the case. 

 



42 

 

3. • Hold the body of the inhaler and unscrew the 
mouthpiece in an anti-clockwise direction. 
• Set the mouthpiece aside on a clean, dry surface. 

 

 

4. Tear along the perforations of the capsule card lengthwise 
then widthwise, as indicated in pictures (1) and (2). 

 

 

5. • Peel back the foil from the capsule card to reveal one 
capsule only. 
• Remove the capsule from the card. 

 

6. • Put the capsule into the inhaler chamber straightaway 
(1). 
• Replace the mouthpiece. 
• Screw the mouthpiece on firmly until it stops. Do not 
overtighten (2). 

 



43 

 

7. • Hold the inhaler with the mouthpiece pointing down 
• Pierce the capsule by pressing firmly the blue button 
with your thumb as far as it will go, then release the 
button. 
• You are now ready to inhale the capsule in 2 separate 
breaths (Steps 8 and 9). 

 

 

 

8. Inhale the capsule – 1st breath: 
Before putting the mouthpiece in your mouth, breathe out 
fully, away from the inhaler. 
Place your mouth over the mouthpiece – to make a tight 
seal. 
Inhale the powder deeply with a single breath. 
Remove the inhaler from your mouth, and hold your 
breath for about 5 seconds. 
Then breathe out normally, away from the inhaler. 

 

 

9. Inhale the capsule – 2nd breath: 
• Take a few normal breaths away from the inhaler. 
• When you are ready, take your 2nd breath by repeating 
Step 8, using the same capsule. 

 
 

10. Unscrew mouthpiece (1) and remove the capsule from the 
chamber (2). 

 

 
 

11. Look at the used capsule. It should appear pierced and 
empty. If it is empty, discard the capsule. 



44 

 

If the capsule is pierced but still contains some powder: 
• Put the capsule back into the inhaler chamber (step 6). 
Put the pierced side of the capsule in first. 
• Replace the mouthpiece and repeat steps 8,9 and 10. 

 

 

If the capsule does not look pierced: 
• Put the capsule back into the inhaler chamber (step 6) 
• Replace the mouthpiece and repeat Steps 7, 8 and 9. 
• After this if the capsule is still full and appears not to be 
pierced, replace the inhaler with the reserve inhaler and 
repeat Steps 2, 3, 6, 7, 8, 9 and 10. 

 

12. Take the other 3 capsules in the same way. 
• So for each remaining capsule, repeat steps 5,6, 7, 8, 9, 
10 and 11. 
• Discard all the empty capsules. 

 

 

13. • Replace the mouthpiece and screw it on firmly until it 
stops. When the full dose (4 capsules) has been inhaled, 
wipe mouthpiece with a clean dry cloth. 
• Do not wash the inhaler with water. 

 

 

14. • Place inhaler back in storage case 
• Twist the top of the case in a clockwise direction until it 
is closed tighly. 

 

 
REMEMBER: 
 
• For inhalation use only. 
• Do not swallow TOBI Podhaler capsules. 
• Only use the inhaler contained in this pack. 
• Always keep the TOBI Podhaler capsules in the capsule card. Only remove a capsule just before 

you are going to use it. Do not store the capsules in the inhaler. 
• Always keep the TOBI Podhaler capsules and device in a dry place. 



45 

• Never place a TOBI Podhaler capsule directly into the mouthpiece of the device. 
• Always hold the device with the mouthpiece pointing down when piercing the capsule. 
• Do not press the piercing button more than once at a time. 
• Never blow into the mouthpiece of the device. 
• Never wash the Podhaler device with water. Keep it dry and store it in its case. 
 
 
Additional information 
Occasionally, very small pieces of the capsule can get past the screen and get into your mouth. 
• If this happens, you may be able to feel these pieces on your tongue. 
• It is not harmful if these pieces are swallowed or inhaled. 
• The chances of the capsule breaking into pieces will be increased if the capsule is accidentally 

pierced more than once or if the device is not held with the mouthpiece pointing down during 
step 7. 

 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 
AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET