4.1. Therapeutic indications

Management of chronic pulmonary infection due to Pseudomonas aeruginosa in patients with cystic fibrosis aged 6 years and older.

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

4.2. Posology and method of administration

Bramitob is intended for inhalation only and not for parenteral use.

Therapy should be initiated by a physician experienced in the management of cystic fibrosis.

The recommended dose for adults and children above 6 years is one single-dose container (300mg) twice daily (morning and evening) for 28 days. The dose interval should be as close as possible to 12 hours. After 28 days of therapy with Bramitob, patients should stop treatment for the next 28 days. Alternate cycles of 28-days of active therapy followed by 28 days without treatment should be maintained (a cycle of 28 days with therapy and 28 days without treatment).

Children under 6 years old

The efficacy and safety of Bramitob have not been demonstrated in patients less than 6 years of age.

Elderly patients

Tobramycin should be used with caution in elderly patients who may have reduced renal function (see section 4.4).

Patients with renal impairment

Tobramycin 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 insufficiency

No 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 dose:

The maximum tolerated daily dose of Bramitob has not been established.

Instructions for opening the container:

1) Bend the single-dose container in both directions

2) Detach the single-dose container from the strip, firstly above then in the middle

3) 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 content of one single-dose container (300mg) emptied into the nebuliser should be administered by inhalation over approximately a 15 minute period. During the pharmaceutical development of Bramitob, the performance of the product was evaluated 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)

The safety and efficacy of Bramitob when administered using other nebulizer system(s) has not been established.

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.

4.3. Contraindications

Administration of Bramitob is contraindicated in all patients with hypersensitivity to tobramycin, to any other aminoglycosides or to any of the excipients listed in section 6.1.

It is also contraindicated in patients receiving potent diuretics, such as furosemide or ethacrynic acid, which have proved to be ototoxic.

4.4. Special warnings and precautions for use

General Warnings

Tobramycin 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.

Bronchospasm

Bronchospasm 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 disorders

Tobramycin 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.

Nephrotoxicity

Although nephrotoxicity has been associated with parenteral aminoglycoside therapy, there was no evidence of nephrotoxicity during clinical trials with tobramycin, however acute kidney injury (AKI) has been reported post-marketing with the use of inhaled tobramycin (see section 4.8). 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.

Ototoxicity

Ototoxicity, 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.

Haemoptysis

Inhalation 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 Resistance

In 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”.

4.5. Interaction with other medicinal products and other forms of interaction

Concurrent and/or sequential use of Bramitob with other medicinal products with nephrotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. Bramitob should not be administered concomitantly with furosemide, ethacrynic acid, urea or intravenous and oral mannitol.

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.

4.6. Fertility, pregnancy and lactation

Bramitob should not be used during pregnancy or lactation unless the benefits to the mother outweigh the risks to the foetus or baby.

Pregnancy

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 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.

Lactation

Systemic 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.

4.7. Effects on ability to drive and use machines

No studies on the effect on the ability to drive and use machines have been performed. On the basis of reported adverse drug reactions, tobramycin is presumed to be unlikely to produce an effect on ability to drive and use machinery.

Nevertheless, since dizziness and/or vertigo may occur, patients who are going to drive or use machinery should be alerted.

4.8. Undesirable effects

In controlled clinical trials (4) and uncontrolled clinical trials (1) with Bramitob (565 patients treated), the most common reactions were those concerning the respiratory tract (cough and dysphonia).

The adverse reactions reported in the clinical trials (see below) are classified as: common (≥1/100 and <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 and <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data).

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

Investigations

Transaminases increased

Uncommon

In controlled clinical trials with other nebulised tobramycin containing medicines, dysphonia and tinnitus were the only undesirable effects reported in significantly more patients treated with tobramycin; (13% tobramycin vs. 7% control) and (3% tobramycin vs. 0% control) respectively. These episodes of tinnitus were transient and resolved without discontinuation of tobramycin therapy, and were not associated with permanent loss of hearing on audiogram testing. The risk of tinnitus did not increase with repeated cycles of exposure to tobramycin.

Additional undesirable effects, some of which are common sequelae of the underlying disease, but where a causal relationship to tobramycin could not be excluded were: sputum discoloured, respiratory tract infection, myalgia, nasal polyps and otitis media.

In addition, cumulative post-marketing data with products containing nebulised tobramycin reported the following adverse reactions (same frequency classification reported above):

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

Somnolence

Very 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

Renal and urinary disorders

Acute kidney injury (AKI) (see section 4.4)

Not known

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, and connective tissue disorders

Back pain

Very rare

General disorders and administration site conditions

Asthenia, pyrexia, chest pain, pain, nausea

Rare

Malaise

Very rare

Investigations

Pulmonary function test decreased

Rare

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 (see 4.4).

Parenteral aminoglycosides have been associated with hypersensitivity, ototoxicity and nephrotoxicity (see sections 4.3 “Contraindications” and 4.4 “Special warnings and precautions for use”).

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:

Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Symptoms

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 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.

Treatment

Acute 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.