Vantobra

1 

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 
 
 
 
 
 
 
 
 
 

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1. NAME OF THE MEDICINAL PRODUCT 
 
Vantobra 170 mg nebuliser solution 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each single-dose ampoule of 1.7 ml contains 170 mg tobramycin.  
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
Nebuliser solution. 
 
A clear to slightly yellow solution. 
 
 
4. CLINICAL PARTICULARS 
 
 
4.1 Therapeutic indications 
 
Vantobra is indicated for the management of chronic pulmonary infection due to Pseudomonas aeruginosa 
in patients aged 6 years and older with cystic fibrosis (CF).  
 
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 Vantobra is the same for all patients within the approved age range, regardless of age or weight. 
The recommended dose is one ampoule (170 mg/1.7 ml) administered twice daily (i.e. total daily dose is 2 
ampoules) for 28 days. The dose interval should be as close as possible to 12 hours and not less than 6 hours.  
Vantobra is taken in alternating cycles of 28 days. A cycle of 28 days of active therapy (on-treatment period) 
and 28 days of rest from treatment (off-treatment period) should be maintained. 
 
Missed doses 
In case of a missed dose with at least 6 hours remaining until the next dose, the patient should inhale the dose 
as soon as possible. If less than 6 hours remain to the next planned dose, the patient should wait for the next 
dose and not inhale more to make up for the missed dose. 
 
Duration of treatment 
Treatment should be continued on a cyclical basis for as long as the physician considers the patient is gaining 
clinical benefit from the treatment taking into account that long-term safety data are not available for 
Vantobra. 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 
There are no data in this population to support a recommendation for or against dose adjustment with 
Vantobra. Please also refer to nephrotoxicity information in section 4.4 and excretion information in section 
5.2. 
 
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 inhaled tobramycin in patients after organ transplantation. No 
recommendation for or against dose adjustment can be made for patients after organ transplantation. 
 
Paediatric population 
There is no relevant use of Vantobra in children below 6 years of age.  
 
Method of administration  
 
Inhalation use. 
 
Vantobra is administered by inhalation using the Tolero nebuliser handset provided in the pack. For detailed 
instructions on use see section 6.6. 
 
Vantobra must not be administered by any other route or using any other device than the one provided in the 
pack. The use of an alternative untested nebuliser system may alter the pulmonary deposition of the active 
substance. And this in turn may alter efficacy and safety of the product. 
 
Where patients are receiving several inhaled medicinal products and chest physiotherapy, it is recommended 
that Vantobra is used last.  
 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance 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.  
 
Auditory toxicity, as measured by complaints of hearing loss or by audiometric evaluations, was observed 
with parenteral aminoglycosides and may be considered also for the inhalation route of administration. 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. Physicians should consider 
the potential for aminoglycosides to cause vestibular and cochlear toxicity and carry out appropriate 
assessments of auditory function during Vantobra therapy.  
 
In patients with a predisposing risk due to previous prolonged systemic aminoglycoside therapy it may be 
necessary to consider audiological assessment before initiating Vantobra therapy. If a patient reports tinnitus 
or hearing loss during aminoglycoside therapy, the physician should consider referring them for audiological 
assessment. 

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Nephrotoxicity 
Nephrotoxicity has been associated with parenteral aminoglycoside therapy. There was no evidence of 
nephrotoxicity during clinical trials with inhaled tobramycin and Vantobra. Caution should be exercised 
when prescribing Vantobra to patients with known or suspected renal dysfunction. According to current 
clinical practice baseline renal function should be assessed. Urea and creatinine levels should be reassessed 
after every 6 complete cycles of Vantobra therapy (180 days of nebulised aminoglycoside therapy).  
 
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 Vantobra, 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 using 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 the use of 
nebulised tobramycin. Bronchospasm should be treated as medically appropriate. 
 
The first dose of Vantobra should be used under supervision of a physician, after taking a bronchodilator if 
this is part of the current regimen for the patient. FEV1 should be measured before and after nebulisation.  
 
If there is evidence of therapy-induced bronchospasm, the physician should carefully evaluate whether the 
benefits of continued use of Vantobra outweighs the risks to the patient. If an allergic response is suspected, 
Vantobra should be discontinued.  
 
Neuromuscular disorders 
Vantobra should be used with great caution in patients with neuromuscular disorders such as Parkinsonism 
or other conditions characterized by myasthenia, including myasthenia gravis, as aminoglycosides may 
aggravate muscle weakness due to a potential curare-like effect on neuromuscular function. 
 
Haemoptysis 
Inhalation of nebulised tobramycin solutions may induce a cough reflex. The treatment with Vantobra in 
patients with active, severe haemoptysis should be initiated only if the benefits of treatment are considered to 
outweigh the risks of inducing further haemorrhage. 
 
Development of resistance 
The development of antibiotic-resistant P. aeruginosa and superinfection with other pathogens represent 
potential risks associated with antibiotic therapy. Development of resistance during inhaled tobramycin 
therapy could limit treatment options during acute exacerbations; this should be monitored. 
 
Other precautions 

 Patients receiving concomitant parenteral aminoglycoside therapy (or any medicine 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.  

 
Safety and efficacy have not been studied in patients colonised with Burkholderia cepacia. 
 
 
4.5 Interaction with other medicinal products and other forms of interaction 
 
No interaction studies have been performed. Based on the interaction profile for tobramycin following 
intravenous and aerosolised administration, concurrent and/or sequential use of Vantobra is not 
recommended with other medicinal products with nephrotoxic or ototoxic potential, such as: 

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- amphotericin B, cefalotin, ciclosporin, tacrolimus, polymyxins (risk of increased nephrotoxicity); 
- platinum compounds (risk of increased nephrotoxicity and ototoxicity);   
 
Concurrent use of Vantobra with diuretic compounds (such as ethacrynic acid, furosemide, urea or mannitol) 
is not recommended. Such compounds can enhance aminoglycoside toxicity by altering antibiotic 
concentrations in serum and tissue (see section 4.4). 
 
Other medicinal products that have been reported to increase the potential toxicity of parenterally 
administered aminoglycosides include: 

- anticholinesterases, botulinum toxin (neuromuscular effects). 
 
In clinical studies patients using inhaled tobramycin 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 limited data from the parenteral use of tobramycin in pregnant women. There are no adequate data 
from the use of tobramycin administered by inhalation in pregnant women. Animal studies do not indicate a 
teratogenic effect of tobramycin (see section 5.3). However, aminoglycosides can cause foetal harm (e.g., 
congenital deafness and nephrotoxicity) when high systemic concentrations are achieved in a pregnant 
woman. Systemic exposure following inhalation of Vantobra is very low (see section 5.2). If Vantobra is 
used during pregnancy, or if the patient becomes pregnant while taking Vantobra, she should be informed of 
the potential hazard to the foetus.  
 
Vantobra should not be used during pregnancy unless the benefits to the mother outweigh the risks to the 
foetus or baby. 
 
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 
Vantobra, 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 
 
Vantobra has no or negligible influence on the ability to drive and use machines.  
 
 
4.8 Undesirable effects 
 
Summary of the safety profile 
In controlled clinical trials with Vantobra the most frequent adverse reactions in cystic fibrosis patients with 
P. aeruginosa infection were cough and dysphonia. 
 
Clinical experience with tobramycin nebuliser solutions reports dysphonia and tinnitus in patients treated 
with tobramycin. The episodes of tinnitus were transient and resolved without discontinuation of tobramycin 
therapy.  

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Occasionally, patients with a history of prolonged previous or concomitant use of intravenous 
aminoglycosides may experience hearing loss. Parenteral aminoglycosides have been associated with 
hypersensitivity, ototoxicity and nephrotoxicity (see section 4.4). 
 
Long-term safety data are not available for Vantobra (see also section 5.1). 
 
Tabulated list of adverse reactions 
Adverse drug reactions reported for tobramycin nebuliser solution are listed in Table 1. 
Adverse drug reactions 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 reactions are presented in order of decreasing seriousness. In addition, the 
corresponding frequency category is provided using the following convention: 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). 
 
Table 1 Adverse reactions 
 
System Organ Class Frequency category Adverse Reactions 
Infections and infestations   
 Rare Laryngitis 
 Very rare Fungal infection  

Oral candidiasis 
Blood and lymphatic system disorders   
 Very rare Lymphadenopathy 
Immune system disorders   
 Very rare Hypersensitivity 
Metabolism and nutrition disorders   
 Rare Anorexia 
Nervous system disorders   
 Rare 

 
Dizziness 
Aphonia 
Headache 

 Very rare Somnolence 
Ear and labyrinth disorders   
 Rare 

 
Hearing loss 
Tinnitus 

 Very rare 
 

Ear pain  
Ear disorder 

Vascular disorders 
 

  

 Rare 
 

Haemoptysis 
Epistaxis 

Respiratory, thoracic and mediastinal 
disorders 

  

 Uncommon 
 

Dyspnoea 
Dysphonia 
Pharyngitis  
Cough 

 Rare Asthma 
Lung disorder  
Chest discomfort 
Productive cough 
Rhinitis 
Bronchospasm 

 Very rare Hypoxia 
Hyperventilation 

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Sinusitis 
Gastrointestinal disorders   
 Rare 

 
Vomiting 
Mouth ulceration 
Nausea 
Dysgeusia 

 Very rare 
 

Diarrhoea 
Abdominal pain 

Skin and subcutaneous tissue disorders   
 Rare Rash 
 Very rare Urticaria 

Pruritus 
Musculoskeletal and connective tissue 
disorders 

  

 Very rare Back pain 
General disorders and administration site 
conditions 

  

 Rare Asthenia 
Pyrexia 
Pain 
Chest pain 

 Very rare Malaise 
Investigations   
 Rare Pulmonary function 

test decreased 
 
 
Paediatric population 
There was no difference in the safety profile between pediatric and adult patient population treated with 
Vantobra. 
 
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 
 
Administration by inhalation results in low systemic bioavailability of tobramycin. Symptoms of aerosol 
overdose may include severe hoarseness. 
 
In the event of accidental ingestion of Vantobra, toxicity is unlikely as tobramycin is poorly absorbed from 
an intact gastrointestinal tract. 
 
In the event of inadvertent administration of Vantobra by the intravenous route, signs and symptoms of 
parenteral tobramycin overdose may occur, including dizziness, tinnitus, vertigo, loss of hearing acuity, 
respiratory distress and/or neuromuscular blockage and renal impairment. 
 
Acute toxicity should be treated with immediate withdrawal of Vantobra and baseline tests of renal function 
should be undertaken. Assessment of tobramycin serum concentrations may be helpful in monitoring 
overdose. In the case of any overdose, the possibility of drug interactions with alterations in the elimination 
of Vantobra or other medicinal products should be considered. 
 
 
5. PHARMACOLOGICAL PROPERTIES 

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8 

 
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 of cystic fibrosis patients exhibits an inhibitory 
action on the local biological activity of nebulised aminoglycosides. This necessitates sputum concentrations 
following treatment with aerosolised tobramycin to be ten to twentyfive-fold above the Minimum Inhibitory 
Concentration (MIC) for both P. aeruginosa growth suppression and control of bactericidal activity. In 
controlled clinical trials, 97% of patients receiving tobramycin nebuliser solution achieved sputum 
concentrations 10-fold of the highest P. aeruginosa MIC cultured from the patient and 95% of patients 
receiving tobramycin nebuliser solution achieved 25-fold of the highest MIC.  
 
Susceptibility 
In the absence of conventional susceptibility breakpoints for the nebulised route of administration, caution 
must be exercised in defining organisms as susceptible or insusceptible to nebulised tobramycin. 
 
In clinical studies with TOBI, most patients with P. aeruginosa isolates with tobramycin MICs < 128 µg/ml 
at baseline showed improved lung function following treatment with TOBI. Patients with a P. aeruginosa 
isolate with MIC 128 µg/ml at baseline are less likely to show a clinical response. However, seven of 13 
patients (54%) in the placebo-controlled trials who acquired isolates with MICs of 128 µg/ml while using 
TOBI had improvement in pulmonary function. 
 
Based upon in-vitro data and/or clinical trial experience, the organisms associated with pulmonary infections 
in CF may be expected to respond to Vantobra therapy as follows: 

Susceptible Pseudomonas aeruginosa 
Haemophilus influenzae 
Staphylococcus aureus 

Insusceptible Burkholderia cepacia 
Stenotrophomonas maltophilia 
Alcaligenes xylosoxidans 

 
Treatment with the 28-days on and 28-days off dose regimen in clinical studies showed a small but clear 
increase in tobramycin, amikacin and gentamicin MICs for P. aeruginosa isolates tested. Each additional 6 
months of treatment resulted in incremental increases similar in magnitude to that observed in the 6 months 
of controlled studies. The most prevalent aminoglycoside resistance mechanism seen in P. aeruginosa 
isolated from chronically infected CF patients is impermeability, defined by a general lack of susceptibility 
to all aminoglycosides. P. aeruginosa isolated from CF patients has also been shown to exhibit adaptive 
aminoglycoside resistance that is characterised by a reversion to susceptibility when the antibiotic is 
removed. 
 
Other information 
There is no evidence that patients treated with up to 18 months with tobramycin nebuliser solution were at a 
greater risk for acquiring B. cepacia, S. maltophilia or A. xylosoxidans, than would be expected in untreated 
patients. Aspergillus species were more frequently recovered from the sputum of treated patients; however, 

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clinical sequelae such as Allergic Bronchopulmonary Aspergillosis (ABPA) were reported rarely and with 
similar frequency as in the control group. 
 
Aerosol characteristics 
 
Table 2: Comparative performance data for the clinical test and reference batches:  
Vantobra /Tolero nebuliser handset1, and TOBI/PARI LC PLUS2.  

Performance parameter/ Drug/Device 
combination* 

Vantobra/Tolero  TOBI/PARI LC 
PLUS 

Total Drug Delivered [mg±SD] 96 ± 4.4 101 ± 8.5  
Fine Particle Mass < 5 µm [mg±SD] 72 ± 6.5 65 ± 7.1 
Drug Delivery Rate [mg/min] 27 ± 5.0 7 ± 0.9 
Mass Median Aerodynamic Diameter 
[µm ± SD] 

3.8 ± 0.3 3.6 ± 0.4 

Geometric Standard Deviation ±SD 1.5 ± 0.0 2.3 ± 0.2 
Nebulisation Time [min] 3.9 ± 0.6  15.3 ± 0.6  
*Results from breath simulation and cascade impactor measurements. 
1 connected with an eBase controller or eFlow rapid controller 
2 connected with a PARI Boy SX compressor 
 
The drug delivery rate of Vantobra with the Tolero nebuliser is independent of the breathing pattern applied 
i.e. adult or child in contrast to the PARI LC PLUS nebuliser. 
 
Clinical efficacy and safety  
Limited data from one controlled clinical study over one treatment cycle indicate that the improvement in 
lung function was maintained above baseline during the 28-day off-treatment period. 
As a result of study 12012.101, lung function improvement FEV1% predicted relative to baseline increased 
by 8.2 ± 9.4% under Vantobra and by 4.8 ± 9.6% under the reference therapy in the first treatment cycle 
showing non-inferior (p=0.0005) efficacy. CFU reduction as an indicator for suppression of P. aeruginosa 
was comparable for Vantobra and the reference product. 
 
 
5.2 Pharmacokinetic properties 
 
Absorption and distribution 
 
The systemic exposure to tobramycin after inhalation of Vantobra is expected to emerge primarily from the 
inhaled portion of the medicinal product as tobramycin is not absorbed to any appreciable extent when 
administered via the oral route. Inhalation of nebulised tobramycin produces high sputum concentrations and 
low plasma levels.  
 
For comparative aerosol data please refer to Table 2 in section 5.1  
 
At the end of a 4-weeks dosing cycle of Vantobra  (170 mg/1.7 ml twice daily) in cystic fibrosis patients, 
maximum tobramycin plasma concentrations (Cmax) of 1.27 ± 0.81 µg/ml were reached at approximately 
one hour after inhalation. Sputum concentrations were higher and more variable with Cmax of 1,951 + 2,187 
µg/g. After administering a single dose of Vantobra 170 mg to healthy volunteers Cmax of 1.1 + 0.4 µg/ml 
were reached after a tmax of approximately 4 hours. 
 
Distribution 
Less than 10% of tobramycin is bound to plasma proteins. 
 
Biotransformation 
Tobramycin is not metabolised and is primarily excreted unchanged in the urine. 
 
Elimination 

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The elimination of tobramycin administered by the inhalation route has not been studied. 
 
Following intravenous administration, systemically absorbed tobramycin is eliminated by glomerular 
filtration. The elimination half-life of tobramycin from serum is approximately 2 hours.  
 
Unabsorbed tobramycin following administration by inhalation is probably eliminated primarily in 
expectorated sputum. 
 
 
5.3 Preclinical safety data 
 
Non-clinical data reveal that the main hazard for humans, based on conventional studies of safety 
pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction and 
development, consists of renal toxicity and ototoxicity. In repeated dose toxicity studies it has been shown 
that target organs of toxicity are the kidneys and vestibular/cochlear functions. In general, toxicity is seen at 
higher systemic tobramycin levels than are achievable by inhalation of the recommended clinical dose. 
 
No reproduction toxicology studies have been conducted with tobramycin administered by inhalation. 
Subcutaneous administration at doses of 100 mg/kg/day in rats and the maximum tolerated dose of 20 
mg/kg/day in rabbits during organogenesis was not teratogenic. Teratogenicity could not be assessed at 
higher parenteral doses in rabbits as they induced maternal toxicity and abortion. Based on available data 
from animals a risk of toxicity (e.g. ototoxicity) at prenatal exposure levels cannot be excluded. Tobramycin 
did not impair fertility in male or female rats at subcutaneous doses up to 100 mg/kg/day.  
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Sodium chloride 
Calcium chloride  
Magnesium sulphate 
Sulphuric acid (for pH adjustment) 
Sodium hydroxide (for pH adjustment) 
Water for injections 
 
6.2 Incompatibilities 
 
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal 
products in the nebuliser.  
 
6.3 Shelf life 
 
3 years  
 
The contents of a single-dose ampoule should be used immediately after opening (see section 6.6).  
 
Stability after opening of the pouch: 4 weeks when stored below 25 °C 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2 °C – 8 °C).  
 
For storage conditions after first opening of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container  

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Vantobra is supplied in polyethylene (PE) ampoules that are packed in sealed aluminium foil pouches (8 
ampoules per pouch).  
 
Outer carton contains: 

• One carton with the medicinal product: 56 ampoules with nebuliser solution in 7 pouches. 
•    One carton with the Tolero nebuliser handset.  

 
6.6 Special precautions for disposal and other handling 

 
The contents of one ampoule should be emptied into the medication reservoir of the Tolero nebuliser handset 
and administered by inhalation until no medicine is left in the reservoir. The Tolero nebuliser handset can be 
operated either with an eBase controller or with the eFlow rapid control unit. The performance parameters 
from in vitro aerosol characterisation studies are identical for the two controllers and are shown in section 
5.1, Table 2. 
 
• Nebulisation should take place in a well ventilated room.  
• The nebuliser handset must be kept horizontally during operation. 
• The patient should sit in an upright position during inhalation. Inhalation should be performed by 

applying a normal breathing pattern without interruption.  
• The Tolero nebuliser handset must be cleaned and disinfected as described in the instructions for use of 

the device. 
 
Vantobra is a clear to slightly yellow solution, but some variability in colour may be observed, which does 
not indicate loss of activity if the product is stored as recommended. 
 
Vantobra solution is a sterile, aqueous preparation for single use only. As it is preservative-free, the contents 
of the whole ampoule should be used immediately after opening and any unused solution should be 
discarded. Opened ampoule should never be stored for re-use. 
 
Use a new Tolero nebuliser handset for each treatment cycle (28 days on-treatment) as provided with the 
medicine. 
 
Any unused medicinal product or waste material should be disposed off in accordance with local 
requirements.  
 
 
7. MARKETING AUTHORISATION HOLDER 
 
PARI Pharma GmbH 
Moosstrasse 3  
D-82319 Starnberg 
Germany 
 
Tel.:   +49 (0) 89 – 74 28 46 - 10  
Fax:   +49 (0) 89 – 74 28 46 - 30 
E-Mail:  info@paripharma.com  
 
 
8. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/14/932/001  
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
18 March 2015 

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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. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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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 
 

 

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A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

Name and address of the manufacturer(s) responsible for batch release 

 
PARI Pharma GmbH 
Lochhamer Schlag 21 
82166 Graefelfing 
GERMANY 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

Medicinal products 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.  

The marketing authorisation holder shall submit the first periodic safety update report for this product 
within 12 months following authorisation.  

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

 
If the submission of a PSUR and the update of a RMP coincide, they can be submitted at the same time. Me

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ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 

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A. LABELLING 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING 
 
OUTER CARTON  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Vantobra 170 mg nebuliser solution 
Tobramycin 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each ampoule of 1.7 ml contains 170 mg tobramycin.  
 
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium chloride, calcium chloride, magnesium sulphate, water for injections, 
sulphuric acid and sodium hydroxide for pH adjustment. 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Package contains  

• One carton with: 56 ampoules with nebuliser solution in 7 pouches. 
• One carton with a Tolero nebuliser handset. 

 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read both the package leaflet of Vantobra and the Instructions for Use of the Tolero nebuliser handset before 
use. 
 
Inhalation use. 
 
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 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 

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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
PARI Pharma GmbH 
Moosstrasse 3  
D-82319 Starnberg 
Germany 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/14/932/001  
 
 
13. BATCH NUMBER 
 
Lot 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Vantobra 170 mg 
 
17. UNIQUE IDENTIFIER – 2D BARCODE  
 
2D barcode carrying the unique identifier included. 
 
18.  UNIQUE IDENTIFIER _ HUMAN READABLE DATA 
 
PC: {number}  
SN: {number}  
NN: {number}  
 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
INNER CARTON CONTAINING THE MEDICINE 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Vantobra 170 mg nebuliser solution 
Tobramycin 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each ampoule of 1.7 ml contains 170 mg tobramycin.  
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium chloride, calcium chloride, magnesium sulphate, water for injections, 
sulphuric acid and sodium hydroxide for pH adjustment. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Package contains 56 ampoules with nebuliser solution in 7 pouches. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read both the package leaflet of Vantobra and the Instructions for Use of the Tolero nebuliser handset before 
use. 
 
Inhalation use. 

 
 

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 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS OR 
WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF APPROPRIATE 

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11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
PARI Pharma GmbH 
Moosstrasse 3  
D-82319 Starnberg 
Germany 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/14/932/001  
 
13. BATCH NUMBER 
 
Lot 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
Vantobra 170 mg 
 

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PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
POUCH  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Vantobra 170 mg nebuliser solution 
 
Tobramycin 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each ampoule of 1.7 ml contains 170 mg tobramycin.  
 
3. LIST OF EXCIPIENTS 
 
Excipients: sodium chloride, calcium chloride, magnesium sulphate, water for injections, 
sulphuric acid and sodium hydroxide for pH adjustment. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
Contains 8 ampoules. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read both the package leaflet of Vantobra and the Instructions for Use of the Tolero nebuliser handset before 
use. 
 
Inhalation use. 

 
 

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 
 
9. SPECIAL STORAGE CONDITIONS 
 
Store in a refrigerator.  
 

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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 
 
PARI Pharma GmbH 
Moosstrasse 3  
D-82319 Starnberg 
Germany 
 
 
12. MARKETING AUTHORISATION NUMBER(S)  
 
EU/1/14/932/001  
 
13. BATCH NUMBER 
 
Lot 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 

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MINIMUM PARTICULARS TO APPEAR ON SMALL IMMEDIATE PACKAGING UNITS 
 
AMPOULE  
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Vantobra 170 mg nebuliser solution 
Tobramycin 
Inhalation use 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
 
PARI Pharma GmbH 
 
 
3. EXPIRY DATE 
 
EXP 
 
4. BATCH NUMBER 
 
Lot 
 
5. OTHER 
 
 

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B. PACKAGE LEAFLET 

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Package leaflet: Information for the patient 
 

Vantobra 170 mg nebuliser solution  
Tobramycin 

 
 
Read all of this leaflet carefully before you start using 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 Vantobra is and what it is used for  
2. What you need to know before you use Vantobra 
3. How to use Vantobra 
4. Possible side effects  
5. How to store Vantobra 
6. Contents of the pack and other information 
 
 
1. What Vantobra is and what it is used for 
 
What Vantobra is 
Vantobra contains an antibiotic medicine called tobramycin. It belongs to a class of antibiotic medicines 
called aminoglycosides. 
 
What Vantobra is used for 
Vantobra is used in patients with cystic fibrosis aged 6 years and older to treat lung infections caused by 
bacteria named Pseudomonas aeruginosa.  
 
Pseudomonas aeruginosa is a bacterium that frequently infects the lungs of cystic fibrosis patients at some 
time during their lives. If the infection is not properly treated, it continues to damage the lungs, causing 
further problems with breathing. 
 
How Vantobra works 
When you inhale Vantobra, the antibiotic can enter directly into your lungs to fight the bacteria causing the 
infection. It works by disrupting the production of proteins that the bacteria need to build their cell walls. 
This damages the bacteria and eventually kills them. 
 
 
2. What you need to know before you use Vantobra  
 
Do not use Vantobra: 
• if you are allergic (hypersensitive) to tobramycin, to any type of aminoglycoside antibiotics, or to any 

of the other ingredients of Vantobra (listed in section 6).  
If this applies to you, tell your doctor before using Vantobra. 

 
Warnings and precautions  
Talk to your doctor if you have ever had any of the following conditions: 
 
• hearing problems (including noises in your ears and dizziness); 
• kidney problems; 

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• 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 (muscle weakness) or Parkinson’s disease. 
If any of these apply to you, tell your doctor before using Vantobra. 
 
If you have problems with your hearing or kidney function, your doctor may take blood samples to monitor 
the amount of Vantobra in your system. 
 
Inhaling medicines can cause chest tightness due to narrowing of the airways, and this can happen with 
Vantobra. Your doctor may ask you to use other appropriate medicines to widen the airways before using 
Vantobra.  
 
Strains of Pseudomonas can become resistant to treatment with an antibiotic over time. This means that 
Vantobra may not work as well as it should over time. Talk to your doctor if you are concerned about this. 
 
If you are also taking tobramycin or another aminoglycoside antibiotic by injection, it may increase the risk 
of side effects and your doctor will monitor for these as appropriate. 
 
Children  
The medicine is not intended for use in children under 6 years of age. 
 
Other medicines and Vantobra 
Tell your doctor or a pharmacist if you are taking or have recently taken any other medicines, including 
medicines obtained without a prescription. 
 
You should not take the following medicines while you are using Vantobra: 
• furosemide, a diuretic (“water tablet”); 
• other medicines with diuretic potential such as urea or mannitol; 
• other medicines which may harm your kidneys or hearing:  

o 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;  

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

 
The following medicines can increase the risks of harmful effects occurring if they are given to you while 
you also take tobramycin or another aminoglycoside antibiotic given by injection: 
• 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, talk to your doctor before you use Vantobra. 
 
You should not mix or dilute Vantobra with any other medicine in your Tolero nebuliser handset which is 
provided together with Vantobra. 
If you are taking several different treatments for cystic fibrosis, you should take them in the following order: 
 
1. Bronchodilator therapy, such as salbutamol 
2. Chest physiotherapy 
3. Other inhaled medicines 
4. Vantobra 

Please check this order with your doctor as well. 
 
Pregnancy and breast-feeding  
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your 
doctor for advice before using this medicine. 
 

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It is not known whether inhaling this medicine while you are pregnant causes side effects. When they are 
given by injection, tobramycin and other aminoglycoside antibiotics can cause harm to an unborn child, such 
as deafness and kidney problems. 
 
If you are breast feeding, you should talk to your doctor before using this medicine. 
 
Driving and using machines 
Vantobra is not expected to affect your ability to drive or use machines. 
 
 
3. How to use Vantobra 
 
Always use this medicine exactly as your doctor has told you. Check with your doctor if you are not sure.  
 
The recommended dose is two ampoules each day (one in the morning and one in the evening) for 28 days.  
 
• The dose is the same for all persons aged 6 years and older. 
• Inhale by mouth the full content of one ampoule in the morning, and one ampoule in the evening using 

the Tolero nebuliser handset. 
• It is best to have an interval as close as possible to 12 hours between doses, but this interval must be at 

least 6 hours. 
• After you have used your medicine for 28 days, you then have a 28-day break, during which you do not 

inhale any Vantobra. You then start another course after the break (as illustrated). 
• It is important that you keep using the medicine twice each day during your 28 days on treatment, and 

that you keep to the 28-day on / 28-day off cycle. 
 
 

 
 
ON Vantobra  OFF Vantobra 
Use Vantobra twice a day for 28 days Do not use any Vantobra for the next 28 days 
 
 
           
         Repeat cycle 
 
Continue using Vantobra on this cyclical basis for as long as your doctor tells you.  
If you have questions about how long to use Vantobra, talk to your doctor or pharmacist. 
 
Preparing Vantobra for inhalation 
 

•   Use Vantobra only with the Tolero nebuliser handset shown in the picture below to make sure you 
inhale the correct dose. Do not use the Tolero nebuliser handset for any other medicine.  

•   Read the Instructions for Use provided with the handset device before use.  
 

 
 
• Make sure you have an eFlowrapid or eBase controller to connect the Tolero nebuliser handset. The 

respective controller can be prescribed by your physician or purchased separately. 

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• Wash your hands thoroughly with soap and water. 
• Remove one ampoule of Vantobra from the aluminium foil pouch just before inhalation.  
• Keep the rest of the medicine refrigerated in the original carton. 
• Lay out all the pieces of your Tolero nebuliser handset on a clean, dry paper or cloth towel. Make 

sure the nebuliser handset is on a flat, stable surface. 
• Assemble the Tolero nebuliser handset as illustrated in the Instructions for Use of the handset device.  
• Hold the ampoule upright and tap lightly before twisting off the head part to avoid spilling. Empty 

the contents of one ampoule into the medication reservoir of the nebuliser handset. 
• Begin your treatment sitting in an upright position, in a well ventilated room. Hold the nebuliser 

handset horizontally and breath normally through your mouth. Avoid breathing through your nose. 
Continue to inhale and exhale comfortably until the treatment is finished. When all of the medicine 
has been delivered, you will hear the “treatment complete” tone. 

• If you need to interrupt your treatment for any reason, press and hold the On/Off button for one full 
second. To re-start the treatment, press and hold the On/Off button again for one full second to 
resume treatment. 

• The Tolero nebuliser handset must be cleaned and disinfected as described in the instructions for use 
of the device. 

• Use a new Tolero nebuliser handset for each treatment cycle (28 days on-treatment) as provided with 
the medicine. 
 

Do not use an alternative untested nebuliser system because it may alter the amount of medicine reaching the 
lungs. This in turn may alter how well the medicine works and its safety. 
 
If you use more Vantobra than you should 
If you inhale too much Vantobra you may get a very hoarse voice. Tell your doctor as soon as possible. If 
Vantobra is swallowed, it is unlikely to cause severe problems as tobramycin is poorly absorbed from the 
stomach, but you should still tell your doctor as soon as possible. 
 
If you forget to use Vantobra  
If you forget to use Vantobra and there are at least 6 hours to your next dose, use your dose as soon as you 
can. Otherwise, wait for your next dose. Do not use a double dose to make up for a forgotten dose. 
 
If you stop using Vantobra  
Do not stop using Vantobra unless your doctor tells you to do so, as your lung infection may not be 
controlled sufficiently and may become worse. 
 
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. 
 
Some side effects can be serious 
• chest tightness with difficulty in breathing (rare, affecting up to 1 in 1,000 people) 
• allergic reactions including hives and itching (very rare, affecting up to 1 in 10,000 people). 
If you experience any of these, stop using Vantobra and tell your doctor straight away.  
 
People with cystic fibrosis have many symptoms of the disease. These may still occur while using Vantobra, 
but should not be as frequent or worse than before. 
 
If your underlying lung disease seems to become worse while you are using Vantobra, tell your doctor 
straight away. 
 

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Other side effects may include: 
Uncommon (may affect up to 1 in 100 people) 
• shortness of breath 
• voice alteration (hoarseness) 
• increased cough 
• sore throat 
 
Rare (may affect up to 1 in 1,000 people) 
• laryngitis (inflammation of the voice box that can cause voice alteration, sore throat and difficulty 

swallowing) 
• Loss of voice 
• headache, weakness 
• nosebleed, runny nose 
• ringing in the ears (normally transient), hearing loss, dizziness 
• coughing up blood, producing more sputum than normally, chest discomfort, asthma, fever 
• taste disturbances, feeling sick (nausea), mouth ulcers, being sick (vomiting), loss of appetite  
• rash 
• chest pain or general pain 
• worsening of lung function test results 
 
Very rare (may affect up to 1 in 10,000 people) 
• fungal infections of the mouth or throat, such as thrush 
• swelling of lymph glands 
• sleepiness 
• ear pain, ear problems  
• hyperventilating, low oxygen levels in your blood, sinusitis 
• diarrhoea, pain in and around the stomach 
• red pustules, papules on the skin 
• nettle rush, itching 
• back pain 
• generally feeling unwell  
 
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 Vantobra 
 

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 ampoule or the pouch or carton after 
EXP. The expiry date refers to the last day of that month. 

 
Store in a refrigerator (2°C - 8°C). If you don’t have a refrigerator available (such as when you are 
transporting your medicine) you can store the carton with the medicine (pouches opened or unopened) 
below 25°C for up to 4 weeks. If the product has been stored at room temperature for longer than 4 
weeks, it has to be disposed according to local requirements. 
  
Do not use this medicine if you notice that it has become cloudy, or if there are particles in the solution. 

  
Never store an opened ampoule. Once opened an ampoule should be used immediately, and any 
remaining product should be discarded. 

 

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


30 

Do not throw away any medicines via household waste. Ask your pharmacist how to throw away 
medicines you no longer use. These measures will help to protect the environment. 

 
 
6. Contents of the pack and other information 
 
What Vantobra contains  
- The active substance is tobramycin. One ampoule contains 170 mg of tobramycin as a single dose.  
- The other ingredient(s) (excipient(s)) are: sodium chloride, calcium chloride, magnesium sulphate, 

water for injections, sulphuric acid and sodium hydroxide for pH adjustment. 
 
What Vantobra looks like and contents of the pack 
Vantobra nebuliser solution is provided in a ready-to-use ampoule.  
 
Vantobra is a clear to slightly yellow coloured solution which can vary to a darker yellow. This does not 
change how Vantobra works provided that the storage instructions have been followed. 
 
Ampoules are packed in  pouches, one pouch contains 8 ampoules which correspond with 4 days of 
treatment. 
 
Vantobra is available together with a Tolero nebuliser handset. It is supplied in a carton that contains two 
inner cartons, one with the medicine (56 ampoules with nebuliser solution in 7 pouches), and one with the 
nebuliser handset. A package is sufficient for one treatment cycle of 28 days. 
 
Marketing Authorisation Holder and Manufacturer 
 
PARI Pharma GmbH 
Moosstrasse 3  
D-82319 Starnberg 
Germany 
 
Tel.:   +49 (0) 89 – 74 28 46 - 10  
Fax:   +49 (0) 89 – 74 28 46 30 
E-Mail:  info@paripharma.com  
 

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. There are also links to other websites about rare diseases and treatments. 

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

	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