TYMBRINEB Nebuliser solution Ref.[49977] Active ingredients: Tobramycin

General warnings

For information on fertility, pregnancy and lactation, see section 4.6.

Tobramycin 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 Tymbrineb, 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 should be given under supervision, using a pre-nebulisation 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 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, Tymbrineb should be discontinued. Bronchospasm should be treated as medically appropriate.

Neuromuscular disorders

Tymbrineb 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.

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 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 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 therapy. In patients with a predisposing risk of ototoxicity due to previous prolonged, systemic aminoglycoside therapy, it may be necessary to consider audiological assessment before initiating tobramycin therapy. The onset of tinnitus warrants caution as it is a sentinel symptom of ototoxicity.

Caution should be exercised when prescribing tobramycin 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.

See also “Monitoring of serum tobramycin concentrations” above.

Haemoptysis

Inhalation of nebulised solutions may induce a cough reflex. The use of tobramycin 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 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).

No interaction studies have been performed.

In clinical studies, patients taking 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 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 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).

Tymbrineb 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 is used during pregnancy, or if the patient becomes pregnant while using tobramycin, she should be informed of the potential hazard to the foetus.

Breast-feeding

Systemic tobramycin is excreted in breast milk. It is not known whether inhaled tobramycin will result in serum concentrations high enough 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 breast-feeding or discontinue tobramycin therapy.

Fertility

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

Tymbrineb has negligible influence on the ability to drive and use machines.

Summary of the safety profile

Two parallel, 24-week, randomised, double-blind, placebo-controlled clinical studies were conducted with tobramycin 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 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; (12.8% tobramycin vs. 6.5% placebo) and (3.1% tobramycin vs. 0% placebo) 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 (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 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, occurring at a higher rate in the Tymbrineb 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 to <1/10); Uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000), including isolated reports.

Table 1. Adverse reactions in clinical trials:

As the duration of exposure to tobramycin 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: 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

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.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal product in the nebuliser.