4.1. Therapeutic indications

Long-term management of chronic pulmonary infection due to Pseudomonas aeruginosa in cystic fibrosis (CF) patients 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

Tobramycin Nebuliser Solution is supplied for use via inhalation and is not for parenteral use. Posology The recommended dose for adults and children is one ampoule twice daily for 28 days. The dose interval should be as close as possible to 12 hours and not less than 6 hours. After 28 days of therapy, patients should stop Tobramycin Nebuliser Solution therapy for the next 28 days. A cycle of 28 days of active therapy and 28 days of rest from treatment should be maintained. Dosage is not adjusted for weight. All patients should receive one ampoule of Tobramycin Nebuliser Solution (300 mg of tobramycin) twice daily. Controlled clinical studies, conducted for a period of 6 months using the following Tobramycin dosage regimen, have shown that improvement in lung function was maintained above baseline during the 28 day rest periods. Tobramycin Dosing Regimen in Controlled Clinical Studies: Cycle 1 Cycle 2 Cycle 3 28 Days 28 Days 28 Days 28 Days 28 Days 28 Days Tobramycin 300 mg twice daily plus standard care Standard care Tobramycin 300 mg twice daily plus standard care Standard care Tobramycin 300 mg twice daily plus standard care Standard care Safety and efficacy for long-term management of chronic pulmonary infection due to Pseudomonas aeruginosa have been assessed in controlled and open label studies for up to 96 weeks (12 cycles), but have not been studied in patients under the age of 6 years, patients with forced expiratory volume in 1 second (FEV1) <25% or>75% predicted, or patients colonised with Burkholderia cepacia . Therapy should be initiated by a physician experienced in the management of cystic fibrosis. Treatment with Tobramycin Nebuliser Solution should be continued on a cyclical basis for as long as the physician considers the patient is gaining clinical benefit from the inclusion of Tobramycin Nebuliser Solution in their treatment regimen. If clinical deterioration of pulmonary status is evident, additional anti-pseudomonal therapy should be considered. Clinical studies have shown that a microbiological report indicating in vitro drug resistance does not necessarily preclude a clinical benefit for the patient. Special populations Elderly (≥ 65 years) There are insufficient data in this population to support a recommendation for or against dose adjustment. Patients with renal impairment There are no data in this population to support a recommendation for or against dose adjustment with Tobramycin Nebuliser Solution. Please also refer to nephrotoxicity information in section 4.4 and excretion information in section 5.2. Patients with hepatic impairment No studies have been performed on patients with hepatic impairment. As tobramycin is not metabolized, 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 Tobramycin Nebuliser Solution in patients after organ transplantation. Paediatric population The safety and efficacy of Tobramycin Nebuliser Solution in children aged less than 6 years have not yet been established. Currently available data are described in section 5.1 but no recommendation on a posology can be made. Method of administration The contents of one ampoule should be emptied into the nebuliser and administered by inhalation over approximately a 15-minute period using a hand-held PARI LC PLUS reusable nebuliser with a suitable compressor. Suitable compressors are those which, when attached to a PARI LC Plus nebuliser, deliver a flow rate of 4-6 l/min and/or a back pressure of 110-217 kPa. The manufacturers' instructions for the care and use of the nebuliser and compressor should be followed. Tobramycin Nebuliser Solution is inhaled whilst the patient is sitting or standing upright and breathing normally through the mouthpiece of the nebuliser. Nose clips may help the patient breathe through the mouth. The patient should continue their standard regimen of chest physiotherapy. The use of appropriate bronchodilators should continue as thought clinically necessary. Where patients are receiving several different respiratory therapies it is recommended that they are taken in the following order: bronchodilator, chest physiotherapy, other inhaled medicinal products, and finally Tobramycin Nebuliser Solution. Maximum tolerated daily dose The maximum tolerated daily dose of Tobramycin Nebuliser Solution has not been established. <summary id="CONTRAINDICATIONS" data-evt="smpcSectionOpen"

4.3. Contraindications

Hypersensitivity to the active substance(s), to any aminoglycoside or to any of the excipients listed in section 6.1. <summary id="CLINICAL_PRECAUTIONS" data-evt="smpcSectionOpen"

4.4. Special warnings and precautions for use

General Warnings For information on pregnancy and lactation see section 4.6. Tobramycin Nebuliser Solution should be used with caution in patients with known or suspected renal, auditory, vestibular or neuromuscular dysfunction, or with severe, active haemoptysis. Monitoring of serum tobramycin concentrations Serum tobramycin concentrations should be monitored in patients with known or suspected auditory or renal dysfunction. If oto- or nephrotoxicity occurs in a patient receiving Tobramycin Nebuliser Solution, tobramycin therapy should be discontinued until serum concentration falls below 2 μg/mL. Serum concentrations of tobramycin should be monitored in patients receiving concomitant parenteral aminoglycoside therapy (or other medications that can affect renal excretion). These patients should be monitored as clinically appropriate. The serum concentration of tobramycin should only be monitored through venipuncture and not finger prick blood sampling. Contamination of the skin of the fingers with tobramycin may lead to falsely increased measurements of serum levels of the drug. This contamination cannot be completely avoided by hand washing before testing. Bronchospasm Bronchospasm can occur with inhalation of medicinal products and has been reported with nebulised tobramycin. The first dose of Tobramycin Nebuliser Solution should be given under supervision, using a pre-nebulisation bronchodilator if this is part of the current regimen for the patient. Forced expiratory volume in 1 second (FEV1) 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. Evidence of bronchospasm in the presence of bronchodilator therapy may indicate an allergic response. If an allergic response is suspected Tobramycin Nebuliser Solution should be discontinued. Bronchospasm should be treated as medically appropriate. Neuromuscular disorders Tobramycin Nebuliser Solution should be used with great caution in patients with known or suspected neuromuscular disorders such as Parkinsonism or other conditions characterised by myasthenia, including myasthenia gravis, as aminoglycosides may aggravate muscle weakness due to a potential curare-like effect on neuromuscular function. Nephrotoxicity Although nephrotoxicity has been associated with parenteral aminoglycoside therapy, there was no evidence of nephrotoxicity during clinical trials with Tobramycin Nebuliser Solution, 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 serum concentrations of tobramycin should be monitored. 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 suggests baseline renal function should be assessed. Urea and creatinine levels should be reassessed after every 6 complete cycles of Tobramycin Nebuliser Solution therapy (180 days of nebulised aminoglycoside therapy). See also “Monitoring of serum tobramycin concentrations” above. Ototoxicity Ototoxicity, manifested as both auditory and vestibular toxicity, has been reported with parenteral aminoglycosides. Vestibular toxicity may be manifested by vertigo, ataxia or dizziness. Ototoxicity, as measured by complaints of hearing loss or by audiometric evaluations, did not occur with nebulised tobramycin therapy 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. Patients with hearing loss frequently reported tinnitus. Physicians should consider the potential for aminoglycosides to cause vestibular and cochlear toxicity and carry out appropriate assessments of auditory function during Tobramycin Nebuliser Solution therapy. In patients with a predisposing risk due to previous prolonged, systemic aminoglycoside therapy it may be necessary to consider audiological assessment before initiating Tobramycin Nebuliser Solution therapy. The onset of tinnitus warrants caution as it is a sentinel symptom of ototoxicity. Caution should be exercised when prescribing Tobramycin Nebuliser Solution to patients with known or suspected auditory or vestibular dysfunction. Physicians should consider an audiological assessment for patients who show any evidence of auditory dysfunction, or who are at increased risk for auditory dysfunction. If a patient reports tinnitus or hearing loss during aminoglycoside therapy the physician should consider referring them for audiological assessment. There is an increased risk of ototoxicity in patients with mitochondrial DNA mutations (particularly the nucleotide 1555 A to G substitution in the 12S rRNA gene), even if aminoglycoside serum levels are within the recommended range during treatment. Alternative treatment options should be considered in such patients. In patients with a maternal history of relevant mutations or aminoglycoside induced deafness, alternative treatments or genetic testing prior to administration, should be considered. See also “Monitoring of serum tobramycin concentrations” above. Haemoptysis Inhalation of nebulised solutions may induce a cough reflex. The use of Tobramycin Nebuliser Solution 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 on nebulised Tobramycin therapy 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). <summary id="INTERACTIONS" data-evt="smpcSectionOpen"

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

No interaction studies have been performed with Tobramycin Nebuliser Solution. In clinical studies, patients taking nebulised Tobramycin concomitantly with dornase alfa, β-agonists, inhaled corticosteroids, and other oral or parenteral anti-pseudomonal antibiotics, demonstrated adverse experience profiles which were similar to those of the control group. Concurrent and/or sequential use of Tobramycin Nebuliser Solution with other medicinal products with neurotoxic, nephrotoxic or ototoxic potential should be avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. Tobramycin Nebuliser Solution should not be administered concomitantly with ethacrynic acid, furosemide, urea or intravenous mannitol. 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). <summary id="PREGNANCY" data-evt="smpcSectionOpen"

4.6. Fertility, pregnancy and lactation

Tobramycin Nebuliser Solution 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). However, aminoglycosides can cause foetal harm (e.g., congenital deafness) when high systemic concentrations are achieved in a pregnant woman. If Tobramycin Nebuliser Solution is used during pregnancy, or if the patient becomes pregnant while taking Tobramycin Nebuliser Solution, she should be informed of the potential hazard to the foetus.

Lactation

Systemic tobramycin is excreted in breast milk. It is not known if administration of Tobramycin Nebuliser Solution will result in serum concentrations high enough for tobramycin to be detected in breast milk. Because of the potential for ototoxicity and nephrotoxicity with tobramycin in infants, a decision should be made whether to terminate nursing or discontinue Tobramycin Nebuliser Solution therapy

Fertility

There are no adequate data about the effect of tobramycin administered by inhalation and patient fertility (male or female). 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

On the basis of reported adverse drug reactions, nebulised Tobramycin is presumed to be unlikely to produce an effect on the ability to drive and use machinery.

4.8. Undesirable effects

Summary of the safety profile Two parallel, 24-week, randomised, double-blind, placebo-controlled clinical studies were conducted with tobramycin nebulised solution in 520 cystic fibrosis patients ranging in age from 6 to 63 years. The most commonly (≥ 10%) reported adverse events in the placebo-controlled studies with tobramycin nebulised solution were cough, pharyngitis, productive cough, asthenia, rhinitis, dyspnoea, pyrexia, lung disorder, headache, chest pain, sputum discoloured, haemoptysis, anorexia, pulmonary function test decreased, asthma, vomiting, abdominal pain, dysphonia, nausea, and weight loss. Most events were reported at similar or higher frequencies in patients receiving placebo. Dysphonia and tinnitus were the only undesirable effects reported in significantly more patients treated with tobramycin nebulised solution; (12.8% tobramycin nebulised solution vs. 6.5% placebo) and (3.1% tobramycin nebulised solution vs. 0% placebo) respectively. These episodes of tinnitus were transient and resolved without discontinuation of tobramycin nebulised solution 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 nebulised solution (see section 4.4 Ototoxicity). Tabulated summary of adverse reactions In the 24-week placebo-controlled studies and their open-label extensions on active treatment, a total of 313, 264 and 120 patients completed treatment with tobramycin nebulised solution for 48, 72 and 96 weeks respectively. Table 1 provides the incidence of treatment-emergent adverse drug reactions, according to the following criteria: reported with an incidence of ≥ 2% for patients receiving tobramycin nebulised solution, occurring at a higher rate in the tobramycin nebulised solution arm, and assessed as drug-related in ≥ 1% of patients. Adverse drug reactions from clinical trials 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, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000) very rare (< 1/10,000), including isolated reports. Table 1 Adverse reactions in clinical trials Adverse reactions Frequency category Infections and infestations Laryngitis Common Ear and labyrinth disorders Tinnitus Common Respiratory, thoracic, and mediastinal disorders Lung disorder Very common Rhinitis Very common Dysphonia Very common Sputum discoloured Very common Musculoskeletal and connective tissue disorders Myalgia Common General disorders and administration site conditions Malaise Common Investigations Pulmonary function test decreased Very common As the duration of exposure to tobramycin nebulised solution increased over the two open-label extension studies, the incidence of productive cough and pulmonary function test decreased appeared to increase; however, the incidence of dysphonia appeared to decline. Overall, the incidence of adverse events related to the following MedDRA System Organ Class (SOC) decreased with increasing exposure to tobramycin nebulised solution: Respiratory, thoracic, and mediastinal disorders, Gastrointestinal disorders, and General disorders and administration site conditions. Adverse reactions derived from spontaneous reports Spontaneously reported adverse reactions, presented below, are reported voluntarily and it is not always possible to reliably establish frequency or a causal relationship to drug exposure. Nervous system disorders Aphonia, dysgeusia Ear and labyrinth disorders Hearing loss Respiratory, thoracic, and mediastinal disorders Bronchospasm, oropharyngeal pain Skin and subcutaneous tissue disorders Hypersensitivity, pruritus, urticaria, rash Renal and urinary disorders Acute kidney injury (AKI) 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 section 4.4). Parenteral aminoglycosides have been associated with hypersensitivity, ototoxicity and nephrotoxicity (see sections 4.3 and 4.4). 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 Yellow Card Scheme at:: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. <summary id="OVERDOSE" data-evt="smpcSectionOpen"

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 Tobramycin Nebuliser Solution, toxicity is unlikely as tobramycin is poorly absorbed from an intact gastrointestinal tract.

In the event of inadvertent administration of Tobramycin Nebuliser Solution by the intravenous route, signs and symptoms of parenteral tobramycin overdose may occur that include dizziness, tinnitus, vertigo, loss of hearing acuity, respiratory distress and/or neuromuscular blockade and renal impairment.

Acute toxicity should be treated with immediate withdrawal of Tobramycin Nebuliser Solution, and baseline tests of renal function should be undertaken. Tobramycin serum concentrations may be helpful in monitoring overdose. In the case of any overdosage, the possibility of drug interactions with alterations in the elimination of Tobramycin Nebuliser Solution or other medicinal products should be considered.