- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
Children under 6 years oldThe efficacy and safety of Bramitob have not been demonstrated in patients less than 6 years of age.
Elderly patientsTobramycin should be used with caution in elderly patients who may have reduced renal function (see section 4.4).
Patients with renal impairmentTobramycin should be used with caution in patients with known or suspected renal dysfunction. Bramitob should be discontinued in the case of nephrotoxicity until serum concentration of tobramycin fall below 2 µg/mL (see section 4.4).
Patients with hepatic insufficiencyNo changes in Bramitob dose are required in hepatic insufficiency.Dosage is not adjusted for body weight. All patients should be administered one single-dose container of Bramitob (300 mg of tobramycin) twice daily.Treatment with tobramycin should be continued on a cyclical basis for as long as the physician considers the patient is gaining clinical benefit from the inclusion of Bramitob in their treatment regimen. If clinical deterioration of pulmonary status is evident, additional anti-pseudomonal therapy should be considered.Method of Administration:The single-dose container should be opened just before use. Any unused solution that is not immediately used should be discarded and not stored for re-use.Administration of Bramitob should be carried out following general hygienic standards. The apparatus used should be clean and working correctly; the nebuliser, that should be for personal use only, should be kept clean and regularly disinfected.For cleaning and disinfection of the nebuliser, refer to the instructions provided with the nebuliser.Maximum tolerated daily doseThe maximum tolerated daily dose of Bramitob has not been established.
Instructions for opening the container:1) Bend the single-dose container in both directions2) Detach the single-dose container from the strip, firstly above then in the middle3) Open the single-dose container by rotating the flap as indicated by the arrow 4) Exerting a moderate pressure on the single-dose container's walls, let the medicinal product flow into the glass tube of the nebuliser.The contents of one single-dose container (300mg) emptied into the nebuliser, should be administered by inhalation over approximately a 15-minute period using a PARI LC PLUS reusable nebuliser equipped with PARI TURBO BOY compressor (drug delivery rate 6.2 mg/min, total drug delivery 92.8 mg, mass median aerodynamic diameter: D10 0.65 µm, D50 3.15µm, D90 8.99µm) or PARI LC SPRINT equipped with compressor PARI BOY Sx (drug delivery rate 6.7 mg/min, total drug delivery 99.8 mg, mass median aerodynamic diameter: D10 0.70 µm, D50 3.36µm, D90 9.41µm)Bramitob is inhaled while the patient is sitting or standing upright and breathing normally through the mouthpiece of the nebuliser. Nose clips may help the patient with breathing through the mouth. The patient should continue their standard regimen of chest physiotherapy. The use of appropriate bronchodilators should continue as thought clinically necessary. In patients receiving several different respiratory therapies, it is recommended that they are taken in the following order: bronchodilator, respiratory physiotherapy, other inhaled medicinal products, and finally Bramitob.Bramitob should not be mixed with other inhalation medicinal products.
General WarningsTobramycin should be used with caution in patients with known or suspected renal, auditory, vestibular or neuromuscular dysfunction, or with severe, active haemoptysis.Renal and eighth cranial nerve function should be closely monitored in patients with known or suspected renal impairment and also in those whose renal function is initially normal but who develop signs of renal dysfunction during therapy. Evidence of impairment in renal, vestibular and/or auditory function requires discontinuation of the drug or dosage adjustment.The serum concentration of tobramycin should only be monitored through venipuncture and not finger prick blood sampling which is a non validated dosing method. It has been observed that contamination of the skin of the fingers from the preparation and nebulisation of tobramycin may lead to falsely increased serum levels of the drug. This contamination cannot be completely avoided by hand washing before testing.
BronchospasmBronchospasm can occur following inhalation of medicinal products and has been reported with nebulised tobramycin. The first dose of Bramitob should be given under medical supervision, using a pre-nebulisation bronchodilator if this is already part of the current treatment regimen for the patient. FEV1 (forced expiratory volume) should be measured before and after nebulisation. If there is evidence of therapy-induced bronchospasm in a patient not receiving a bronchodilator, the test should be repeated on a separate occasion, using a bronchodilator. Onset of bronchospasm in the presence of bronchodilator therapy may indicate an allergic reaction. Should an allergic reaction be suspected, Bramitob should be discontinued. Bronchospasm should be treated as clinically appropriate.
Neuromuscular disordersTobramycin should be used with great caution in patients with neuromuscular disorders, such as parkinsonism or other conditions characterised by myasthenia, including myasthenia gravis, as aminoglycosides may worsen muscular weakness due to a potential curare-like effect on the neuromuscular function.
NephrotoxicityAlthough nephrotoxicity has been associated with parenteral aminoglycoside therapy, there was no evidence of nephrotoxicity during clinical trials with tobramycin. The product should be used with caution in patients with known or suspected renal dysfunction and tobramycin serum concentrations should be monitored, e.g. serum level assays after two or three doses should be performed, so that the dosage could be adjusted if necessary, and also at three to four day intervals during therapy. In the event of changing renal function, more frequent serum levels should be obtained and the dosage or dosage intervals adjusted. Patients with severe renal impairment, i.e. serum creatinine > 2 mg/dl (176.8 µmol/l) were not included in the clinical studies.Current clinical practice recommends that baseline renal function should be assessed. Furthermore, the renal function should be periodically reassessed, by regularly monitoring urea and creatinine levels at least every 6 full cycles of therapy with tobramycin (180-day treatment with nebulised tobramycin). If there is evidence of nephrotoxicity, therapy with tobramycin should be discontinued until the drug minimum serum concentrations fall below 2 μg/ml. Tobramycin therapy may then be resumed following medical advice. Patients receiving concomitant parenteral aminoglycoside therapy should be strictly monitored, due to the risk of cumulative toxicity.Monitoring of renal function is particular important in elderly patients who may have reduced renal function that may not be evident in the results of routine screening tests, such as blood urea or serum creatinine. A creatinine clearance determination may be more useful.Urine should be examined for increased excretion of protein, cells and casts. Serum creatinine or creatinine clearance (preferred over blood urea) should be measured periodically.
OtotoxicityOtotoxicity, manifested as both auditory and vestibular toxicity has been reported with the parenteral aminoglycosides. Vestibular toxicity may be manifested by vertigo, ataxia or dizziness.During controlled clinical studies with tobramycin, modest hypoacusia and vertigo were observed, while with other nebulised tobramycin containing medicines auditory toxicity, as measured by complaints of hearing loss or by audiometric evaluations did not occur during controlled clinical studies. In open label studies and post-marketing experience, some patients with a history of prolonged previous or concomitant use of intravenous aminoglycosides have experienced hearing loss.The physician should consider the possibility that aminoglycosides may cause vestibular and cochlear toxicity and should assess auditory function throughout the treatment period with Bramitob. In patients with a predisposing risk due to previous prolonged systemic therapy with aminoglycosides, it may be necessary to consider audiological assessment before starting therapy with tobramycin. The occurrence of tinnitus warrants caution, since it represents an ototoxic symptom. If the patient reports about tinnitus or hearing loss during the therapy with aminoglycosides, the physician should consider whether audiologic tests are necessary. When feasible, it is recommended that serial audiograms are performed in patients on continuous therapy, which are at particular high risk of ototoxicity. Patients receiving concomitant parenteral therapy with aminoglycosides should be monitored as clinically appropriate, taking into account the risk of cumulative toxicity.
HaemoptysisInhalation of nebulised solutions may induce a cough reflex. The use of nebulised Bramitob in patients with active, severe haemoptysis should be undertaken only if the benefits of treatment are considered to outweigh the risks of inducing further haemorrhage.
Microbial ResistanceIn clinical studies, some patients treated with nebulised tobramycin showed an increase in aminoglycoside Minimum Inhibitory Concentrations for P. aeruginosa isolates tested. There is a theoretical risk that patients being treated with nebulised tobramycin may develop P. aeruginosa isolates resistant to intravenous tobramycin (see section 5.1 Pharmacodynamic properties). In clinical trials there is no data in patients with Burkholderia cepacia infections.For information related to administration during pregnancy and lactation see section 4.6 Pregnancy and lactation.
Other medicinal products that have been reported to increase the potential toxicity of parenterally administered aminoglycosides include:Amphotericin B, cephalotin, ciclosporin, tacrolimus, polymyxins (risk of increased nephrotoxicity); platinum compounds (risk increased nephrotoxicity and ototoxicity).Anticholinesterases, botulinum toxin: Due to their neuromuscular effects, the combination with tobramycin should be avoided.
Others:In clinical studies, patients taking nebulised tobramycin concomitantly with dornase alfa, mucolytic, B agonists, inhaled corticosteroids, and other oral or parenteral anti-pseudomonal antibiotics, showed adverse events similar to the patients of the control group.
PregnancyThere 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 Preclinical data). However, aminoglycosides can cause foetal harm (e.g., congenital deafness) when high systemic concentrations are achieved in a pregnant woman. If Bramitob is used during pregnancy, or if the patient becomes pregnant while taking Bramitob, she should be informed of the potential hazard to the foetus.
LactationSystemic tobramycin is excreted in breast milk. It is not known if inhaled tobramycin will result in serum concentrations high enough for tobramycin to be detected in breast milk. Because of the potential risk for ototoxicity and nephrotoxicity with tobramycin in infants, a decision should be made whether to terminate nursing or discontinue Bramitob therapy.
|System Organ Class||Adverse Reaction||Frequency|
|Infections & Infestations||Fungal infection, oral candidiasis||Uncommon|
|Nervous system disorders||Headache||Uncommon|
|Ear and labyrinth disorders||Vertigo, hypoacusis, deafness neurosensory (see section 4.4)||Uncommon|
|Respiratory, thoracic and mediastinal disorders||Cough, dysphonia||Common|
|Forced expiratory volume decreased, dyspnoea, rales, haemoptysis, oropharyngeal pain, productive cough||Uncommon|
|Gastrointestinal disorders||Salivary hypersecretion, glossitis, abdominal pain upper, nausea||Uncommon|
|Skin and subcutaneous tissue disorders||Rash||Uncommon|
|General disorders and administration site conditions||Asthenia, chest discomfort, mucosal dryness||Uncommon|
|System Organ Class||Adverse Reaction||Frequency|
|Infections & Infestations||Laryngitis||Rare|
|Fungal infection, oral candidiasis||Very rare|
|Blood and lymphatic system disorders||Lymphadenopathy||Very rare|
|Immune system disoders||Hypersensitivity||Very rare|
|Metabolism and nutrition disorders||Anorexia||Rare|
|Nervous system disorders||Dizziness, headache, aphonia||Rare|
|Ear and labyrinth disorders||Tinnitus, hearing loss (see section 4.4)||Rare|
|Ear disorders, ear pain||Very rare|
|Respiratory, thoracic and mediastinal disorders||Cough, pharyngitis, dysphonia, dyspnoea||Uncommon|
|Bronchospasm, chest discomfort, lung disorder, haemoptysis, epistaxis, rhinitis, asthma, productive cough||Rare|
|Hyperventilation, hypoxia, sinusitis||Very rare|
|Gastrointestinal disorders||Dysgeusia, mouth ulceration vomiting, nausea||Rare|
|Diarrhoea, abdominal pain||Very rare|
|Skin and subcutaneous tissue disorders||Rash||Rare|
|Urticaria, pruritus||Very rare|
|Musculo-skeletal, connective tissue and bone disorders||Back pain||Very rare|
|General disorders and administration site conditions||Asthenia, pyrexia, chest pain, pain, nausea||Rare|
|Investigations||Pulmonary function test decreased||Rare|
Reporting of suspected adverse reactionsReporting 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 Yellow Card Scheme at www.mhra.gov.uk/yellowcard.
SymptomsAdministration by inhalation results in low systemic bioavailability of tobramycin. Symptoms of aerosol overdose may include severe hoarseness.In the event of accidental ingestion of Bramitob, toxicity is unlikely as tobramycin is poorly absorbed from an intact gastrointestinal tract.In the event of inadvertent intravenous administration of Bramitob, signs and symptoms of parenteral tobramycin overdose may occur, such as dizziness, tinnitus, vertigo, hearing loss, respiratory distress and/or neuromuscular blockade and renal impairment.
TreatmentAcute toxicity should be treated with immediate withdrawal of Bramitob, and baseline tests of renal function should be carried out. Tobramycin serum concentrations may be helpful in monitoring overdose. In case of any overdose, the possibility of drug interactions with alterations in the elimination of Bramitob or other medicinal products should be considered.
BreakpointsEstablished susceptibility breakpoints for parenteral administration of tobramycin are inappropriate in the aerosolised administration of the medicinal product. Cystic fibrosis (CF) sputum exhibits an inhibitory action on the local biological activity of nebulised aminoglycosides. This necessitates sputum concentrations of aerosolised tobramycin to be some ten and twentyfive fold above the Minimum Inhibitory Concentration (MIC) for, respectively, P. aeruginosa growth suppression and bactericidal activity. In controlled clinical trials, 90% of patients receiving tobramycin achieved sputum concentrations 10 fold the highest P. aeruginosa MIC cultured from the patient, and 84% of patients receiving tobramycin achieved 25 fold the highest MIC. Clinical benefit is still achieved in a majority of patients who culture strains with MIC values above the parenteral breakpoint.
SusceptibilityIn 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 inhaled tobramycin, most patients (88%) with P. aeruginosa isolates with tobramycin MICs <128 µg/mL at baseline showed improved lung function following treatment with tobramycin. Patients with a P. aeruginosa isolate with a MIC ≥ 128 µg/mL at baseline are less likely to show a clinical response. Based upon in vitro data and/or clinical trial experience, the organisms associated with pulmonary infections in CF may be expected to respond to tobramycin therapy as follows:
|Susceptible||Pseudomonas aeruginosa Haemophilus influenzae Staphylococcus aureus|
|Insusceptible||Burkholderia cepacia Stenotrophomonas maltophilia Alcaligenes xylosoxidans|
Other InformationIn controlled clinical studies, treatment with Bramitob carried out according to alternate cycles as described above, led to an improvement in lung function, with results maintained above baseline throughout therapy and 28 day periods off therapy.In clinical trials with tobramycin there are no data in patients aged less than 6 years.There is no evidence that patients treated with up to 18 months with tobramycin were at a greater risk for acquiring B. cepacia, S. maltophilia or A. xylosoxidans, than would be expected in patients not treated with tobramycin. Aspergillus species were more frequently recovered from the sputum of patients who received tobramycin; however, clinical sequelae such as Allergic Bronchopulmonary Aspergillosis (ABPA) were reported rarely and with similar frequency as in the control group.
Absorption and distributionFollowing oral administration only 0.3-0.5% of the drug appears in urine to prove systemic absorption. After administration via nebuliser in 6 cystic fibrosis patients, mean absolute bioavailability was about 9.1% of the dose. Systemic absorption of tobramycin is very low when administered by aerosol inhalation, with a limited uptake of the inhaled drug into the systemic circulation, it is estimated that approximately 10% of the mass of drug initially nebulised is deposited in the lungs and the remaining 90% either remains in the nebuliser, is impacted on the oro-pharynx and swallowed, or is exhaled into the atmosphere.Sputum concentrations: Ten minutes after inhalation of the first 300 mg dose of Bramitob, the average sputum concentration of tobramycin was 695.6 μg/g (range: 36 to 2,638 μg/g). Tobramycin does not accumulate in sputum; after 20 weeks of therapy with the Bramitob regimen, the average sputum concentration of tobramycin 10 minutes after inhalation was 716.9 μg/g (range: 40 to 2,530 μg/g). High variability of sputum tobramycin concentrations was observed. Two hours after inhalation, sputum concentrations declined to approximately 14% of tobramycin levels measured at 10 minutes after inhalation.Serum concentrations: The median serum concentration of tobramycin 1 hour after inhalation of a single 300 mg dose of Bramitob by CF patients was 0.68 μg/mL (range: 0.06μg/mL 1.89μg/mL). After 20 weeks of therapy on the tobramycin regimen, the median serum tobramycin concentration 1 hour after dosing was 1.05 μg/mL (range: BLQ- 3.41μg/mL).
EliminationThe elimination of tobramycin administered by the inhalation route has not been studied.Following intravenous administration, systemically absorbed tobramycin is eliminated principally by glomerular filtration. The elimination half-life of tobramycin from serum is approximately 2 hours. Less than 10% of tobramycin is bound to plasma proteins.Unabsorbed tobramycin following tobramycin administration is probably eliminated primarily in expectorated sputum.
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