4.1. Therapeutic indications

TOBI Podhaler is indicated for the suppressive therapy of chronic pulmonary infection due to Pseudomonas aeruginosa in adults and children aged 6 years and older with cystic fibrosis.

See sections 4.4 and 5.1 regarding data in different age groups.

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

4.2. Posology and method of administration

Posology

The dose of TOBI Podhaler is the same for all patients within the approved age range, regardless of age or weight. The recommended dose is 112 mg tobramycin (4 x 28 mg capsules), administered twice daily for 28 days. TOBI Podhaler is taken in alternating cycles of 28 days on treatment followed by 28 days off treatment. The two doses (of 4 capsules each) should be inhaled as close as possible to 12 hours apart and not less than 6 hours apart.

Missed doses

In case of missed dose with at least 6 hours until the next dose, the patient should take the dose as soon as possible. Otherwise, the patient should wait for the next dose and not inhale more capsules to make up for the missed dose.

Duration of treatment

Treatment with TOBI Podhaler should be continued on a cyclical basis for as long as the physician considers the patient is gaining clinical benefit from the treatment with TOBI Podhaler. If clinical deterioration of pulmonary status is evident, additional or alternative anti-pseudomonal therapy should be considered. See also information on clinical benefit and tolerability in sections 4.4, 4.8 and 5.1.

Special populations

Elderly patients (≥65 years)

There are insufficient data in this population to support a recommendation for or against dose adjustment.

Renal impairment

Tobramycin is primarily excreted unchanged in the urine and renal function is expected to affect the exposure to tobramycin. Patients with serum creatinine 2 mg/dl or more and blood urea nitrogen (BUN) 40 mg/dl or more have not been included in clinical studies and there are no data in this population to support a recommendation for or against dose adjustment with TOBI Podhaler. Caution should be exercised when prescribing TOBI Podhaler to patients with known or suspected renal dysfunction.

Please also refer to nephrotoxicity information in section 4.4.

Hepatic impairment

No studies have been performed on patients with hepatic impairment. As tobramycin is not metabolised, an effect of hepatic impairment on the exposure to tobramycin is not expected.

Patients after organ transplantation

Adequate data do not exist for the use of TOBI Podhaler in patients after organ transplantation. No recommendation for or against dose adjustment can be made for patients after organ transplantation.

Paediatric population

The safety and efficacy of TOBI Podhaler in children aged under 6 years have not been established. No data are available.

Method of administration

Inhalation use.

TOBI Podhaler is administered by inhalation using the Podhaler device (see section 6.6 for detailed instructions for use). It must not be administered by any other route or using any other inhaler.

Caregivers should provide assistance to children starting TOBI Podhaler treatment, particularly those aged 10 years or younger, and should continue to supervise them until they are able to use the Podhaler device properly without help.

TOBI Podhaler capsules must not be swallowed. Each TOBI Podhaler capsule should be inhaled with two breath-hold manoeuvres and checked to ensure it is empty.

Where patients are receiving several different inhaled medicinal products and chest physiotherapy, it is recommended that TOBI Podhaler is taken last.

4.3. Contraindications

Hypersensitivity to the active substance and any aminoglycoside, or to any of the excipients listed in section 6.1.

4.4. Special warnings and precautions for use

Ototoxicity

Ototoxicity, manifested as both auditory toxicity (hearing loss) and vestibular toxicity, has been reported with parenteral aminoglycosides. Vestibular toxicity may be manifested by vertigo, ataxia or dizziness. Tinnitus may be a sentinel symptom of ototoxicity, and therefore the onset of this symptom warrants caution.

Hearing loss and tinnitus were reported by patients in the TOBI Podhaler clinical studies (see section 4.8). Caution should be exercised when prescribing TOBI Podhaler to patients with known or suspected auditory or vestibular dysfunction.

In patients with any evidence of auditory dysfunction, or those with a predisposing risk, it may be necessary to consider audiological assessment before initiating TOBI Podhaler therapy.

Risk of ototoxicity due to mitochondrial DNA variants

Cases of ototoxicity with aminoglycosides have been observed in patients with certain variants in the mitochondrially encoded 12S rRNA gene (MT-RNR1), particularly the m.1555A>G variant. Ototoxicity occurred in some patients even when their aminoglycoside serum levels were within the recommended range. In case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial DNA variant in the patient, it may be necessary to consider alternative treatments other than aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the severity of infection and lack of safe and effective alternative therapies.

If a patient reports tinnitus or hearing loss during TOBI Podhaler therapy the physician should consider referring them for audiological assessment.

See also “Monitoring of serum tobramycin concentrations” below.

Nephrotoxicity

Nephrotoxicity has been reported with the use of parenteral aminoglycosides. Nephrotoxicity was not observed during TOBI Podhaler clinical studies, however acute kidney injury (AKI) has been reported post-marketing with the use of inhaled tobramycin (see section 4.8). Caution should be exercised when prescribing TOBI Podhaler to patients with known or suspected renal dysfunction. Baseline renal function should be assessed. Urea and creatinine levels should be reassessed after every 6 complete cycles of TOBI Podhaler therapy.

See also section 4.2 and “Monitoring of serum tobramycin concentrations” below.

Monitoring of serum tobramycin concentrations

Patients with known or suspected auditory or renal dysfunction should be monitored for serum tobramycin concentrations. If oto- or nephrotoxicity occurs in a patient receiving TOBI Podhaler, tobramycin therapy should be discontinued until serum concentration falls below 2 µg/ml.

Serum concentrations greater than 12 µg/ml are associated with tobramycin toxicity and treatment should be discontinued if concentrations exceed this level.

The serum concentration of tobramycin should only be monitored through validated methods. Finger prick blood sampling is not recommended due to the risk of contamination of the sample.

Bronchospasm

Bronchospasm can occur with inhalation of medicinal products and has been reported with TOBI Podhaler in clinical studies. Bronchospasm should be treated as medically appropriate.

The first dose of TOBI Podhaler should be given under supervision, after using a bronchodilator if this is part of the current regimen for the patient. FEV1 should be measured before and after inhalation of TOBI Podhaler.

If there is evidence of therapy-induced bronchospasm, the physician should carefully evaluate whether the benefits of continued use of TOBI Podhaler outweigh the risks to the patient. If an allergic response is suspected, TOBI Podhaler should be discontinued.

Cough

Cough was reported with use of TOBI Podhaler in clinical studies. Based on clinical trial data the inhalation powder TOBI Podhaler was associated with a higher reported rate of cough compared with tobramycin nebuliser solution (TOBI). Cough was not related to bronchospasm. Children below the age of 13 years may be more likely to cough when treated with TOBI Podhaler compared with older subjects.

If there is evidence of continued therapy-induced cough with TOBI Podhaler, the physician should consider whether an approved tobramycin nebuliser solution should be used as an alternative treatment. Should cough remain unchanged, other antibiotics should be considered.

Haemoptysis

Haemoptysis is a complication in cystic fibrosis and is more frequent in adults. Patients with haemoptysis (>60 ml) were excluded from the clinical studies so no data exist on the use of TOBI Podhaler in these patients. This should be taken into account before prescribing TOBI Podhaler, considering the inhalation powder TOBI Podhaler was associated with a higher rate of cough (see above). The use of TOBI Podhaler in patients with clinically significant haemoptysis should be undertaken or continued only if the benefits of treatment are considered to outweigh the risks of inducing further haemorrhage.

Other precautions

Patients receiving concomitant parenteral aminoglycoside therapy (or any medication affecting renal excretion, such as diuretics) should be monitored as clinically appropriate taking into account the risk of cumulative toxicity. This includes monitoring of serum concentrations of tobramycin. In patients with a predisposing risk due to previous prolonged, systemic aminoglycoside therapy it may be necessary to consider renal and audiological assessment before initiating TOBI Podhaler therapy.

See also “Monitoring of serum tobramycin concentrations” above.

Caution should be exercised when prescribing TOBI Podhaler to patients with known or suspected neuromuscular disorders such as myasthenia gravis or Parkinson's disease. Aminoglycosides may aggravate muscle weakness because of a potential curare-like effect on neuromuscular function.

The development of antibiotic-resistant P. aeruginosa and superinfection with other pathogens represent potential risks associated with antibiotic therapy. In clinical studies, some patients on TOBI Podhaler therapy showed an increase in aminoglycoside minimum inhibitory concentrations (MIC) for P. aeruginosa isolates tested. MIC increases observed were in large part reversible during off-treatment periods.

There is a theoretical risk that patients being treated with TOBI Podhaler may develop P. aeruginosa isolates resistant to intravenous tobramycin over time (see section 5.1). Development of resistance during inhaled tobramycin therapy could limit treatment options during acute exacerbations; this should be monitored.

Data in different age groups

In a 6-month (3 treatment cycles) study of TOBI Podhaler versus tobramycin nebuliser solution, which included a majority of tobramycin-experienced adult patients with chronic pulmonary P. aeruginosa infection, the suppression of sputum P. aeruginosa density was similar across age groups in both arms; however the increase from baseline FEV1 was larger in younger age groups (6 - <20) than in the adult subgroup (20 years and older) in both arms. See also section 5.1 for the profile of response of TOBI Podhaler compared to tobramycin nebuliser solution. Adult patients tended to discontinue more frequently for tolerability reasons with TOBI Podhaler than with the nebuliser solution. See also section 4.8.

If clinical deterioration of pulmonary status is evident, additional or alternative anti-pseudomonal therapy should be considered.

Observed benefits on lung function and P. aeruginosa suppression should be assessed in the context of the patient's tolerance of TOBI Podhaler.

Safety and efficacy have not been studied in patients with forced expiratory volume in 1 second (FEV1) <25% or >80% predicted, or patients colonised with Burkholderia cepacia.

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

No interaction studies have been performed with TOBI Podhaler. Based on the interaction profile for tobramycin following intravenous and aerosolised administration, concurrent and/or sequential use of TOBI Podhaler is not recommended with other medicinal products with nephrotoxic or ototoxic potential.

Concomitant use of TOBI Podhaler with diuretic compounds (such as ethacrynic acid, furosemide, urea or intravenous mannitol) is not recommended. Such coumpounds can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue.

See also information on previous and concomitant use of systemic aminoglycosides and diuretics in section 4.4.

Other medicinal products that have been reported to increase the potential toxicity of parenterally administered aminoglycosides include:

- amphotericin B, cefalotin, ciclosporin, tacrolimus, polymyxins (risk of increased nephrotoxicity);

- platinum compounds (risk of increased nephrotoxicity and ototoxicity);

- anticholinesterases, botulinum toxin (neuromuscular effects).

In clinical studies, patients receiving TOBI Podhaler continued to take dornase alfa, bronchodilators, inhaled corticosteroids and macrolides, no evidence of drug interactions with these medicines was identified.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no adequate data on the use of tobramycin via inhalation in pregnant women. Animal studies with tobramycin do not indicate a teratogenic effect (see section 5.3). However, aminoglycosides can cause foetal harm (e.g. congenital deafness) when high systemic concentrations are achieved in a pregnant woman. Systemic exposure following inhalation of TOBI Podhaler is very low, however TOBI Podhaler should not be used during pregnancy unless clearly necessary, i.e. when the benefits to the mother outweigh the risks to the foetus. Patients who use TOBI Podhaler during pregnancy, or become pregnant while taking TOBI Podhaler, should be informed of the potential hazard to the foetus.

Breast-feeding

Tobramycin is excreted in human breast milk after systemic administration. The amount of tobramycin excreted in human breast milk after administration by inhalation is not known, though it is estimated to be very low considering the low systemic exposure. Because of the potential for ototoxicity and nephrotoxicity in infants, a decision should be made whether to terminate breast-feeding or discontinue treatment with TOBI Podhaler, taking into account the importance of the treatment to the mother.

Fertility

No effect on male or female fertility was observed in animal studies after subcutaneous administration (see section 5.3).

4.7. Effects on ability to drive and use machines

TOBI Podhaler has no or negligible influence on the ability to drive and use machines.

4.8. Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions in the main safety, active-controlled clinical study with TOBI Podhaler versus tobramycin nebuliser solution in cystic fibrosis patients with P. aeruginosa infection were cough, productive cough, pyrexia, dyspnoea, oropharyngeal pain, dysphonia and haemoptysis.

In the placebo-controlled study with TOBI Podhaler, the adverse reactions for which reported frequency was higher with TOBI Podhaler than with placebo were pharyngolaryngeal pain, dysgeusia and dysphonia.

The vast majority of adverse reactions reported with TOBI Podhaler were mild or moderate, and severity did not appear to differ between cycles or between the entire study and on-treatment periods.

Tabulated summary of adverse reactions

Adverse drug reactions in Table 1 are listed according to system organ classes in MedDRA. Within each system organ class, the adverse drug reactions are ranked by frequency, with the most frequent reactions first. Within each frequency grouping, adverse drug reactions are presented in order of decreasing seriousness. In addition, the corresponding frequency category for each adverse drug reaction is based on the following convention (CIOMS III): very common (≥1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known: cannot be estimated from the available data.

The frequencies in Table 1 are based on the reporting rates from the active-controlled study.

Table 1 Adverse reactions

Adverse reactions

Frequency category

Ear and labyrinth disorders

Hearing loss

Common

Tinnitus

Common

Vascular disorders

Haemoptysis

Very common

Epistaxis

Common

Respiratory, thoracic and mediastinal disorders

Dyspnoea

Very common

Dysphonia

Very common

Productive cough

Very common

Cough

Very common

Wheezing

Common

Rales

Common

Chest discomfort

Common

Nasal congestion

Common

Bronchospasm

Common

Aphonia

Common

Sputum discoloured

Not known

Gastrointestinal disorders

Oropharnygeal pain

Very common

Vomiting

Common

Diarrhoea

Common

Throat irritation

Common

Nausea

Common

Dysgeusia

Common

Skin and subcutaneous tissue disorders

Rash

Common

Musculoskeletal and connective tissue disorders

Musculoskeletal chest pain

Common

Renal and urinary disorders

Acute kidney injury (AKI)

Not known

General disorders and administration site conditions

Pyrexia

Very common

Malaise

Not known

Description of selected adverse drug reactions

Cough was the most frequently reported adverse reaction in both clinical studies. However, no association was observed in either clinical study between the incidence of bronchospasm and cough events.

In the active-controlled study, audiology testing was performed in selected centres accounting for about a quarter of the study population. Four patients in the TOBI Podhaler treatment group experienced significant decreases in hearing which were transient in three patients and persistent in one case.

In the active-controlled open-label study, patients aged 20 years and older tended to discontinue more frequently with TOBI Podhaler than with the nebuliser solution; discontinuations due to adverse events accounted for about half of the discontinuations with each formulation. In children under 13 years of age, discontinuations were more frequent in the TOBI nebuliser solution arm whereas in patients aged 13 to 19, discontinuation rates with both formulations were similar.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

Adverse reactions specifically associated with overdose of TOBI Podhaler have not been identified. The maximum tolerated daily dose of TOBI Podhaler has not been established. Tobramycin serum concentrations may be helpful in monitoring overdosage. In case of signs of acute toxicity, immediate withdrawal of TOBI Podhaler and testing of renal function are recommended. In the event of accidental oral ingestion of TOBI Podhaler capsules, toxicity is unlikely as tobramycin is poorly absorbed from an intact gastrointestinal tract. Haemodialysis may be helpful in removing tobramycin from the body.