Dilaterol

Tymbrineb Nebuliser Solution is used for the long-term management of chronic pulmonary infection due to Pseudomonas aeruginosa in patients aged six years and older with cystic fibrosis (CF).

The official guidance on the appropriate use of antibacterial agents should be considered.

Tymbrineb Nebuliser Solution is indicated in adults, adolescents and children aged six years and older.

Tymbrineb Nebuliser Solution is for inhalation use and is not intended for parenteral use.

Posology

The recommended daily dose for adults and children is one ampoule twice daily for 28 days, with a dose interval as close as possible to 12 hours and not less than six hours. After completion of the 28-day treatment, patients should stop using Tymbrineb Nebuliser Solution for the next 28 days. Patients should maintain a cycle of 28 days of active treatment and 28 days of rest from treatment. Dosage is not adjusted for weight, so all patients should receive one ampoule of Dilaterol 300 mg twice daily.

Tymbrineb Dosing Regimen in Controlled Clinical Studies

Data from controlled clinical studies, over a period of six months using the following regimens, have shown that the improvement in lung function was maintained above baseline during the 28-day rest period.

In addition, safety and efficacy have been assessed for up to 96 weeks (12 cycles). Safety and efficacy have not been assessed in patients under the age of six years, in patients with forced expiratory volume in one second (FEV₁) <25% or >75% predicted or in patients colonised with Burkholderia cepacia.

Therapy should be initiated by a physician with experience in the management of CF. Dilaterol treatment should be continued on a cyclical basis for as long as the physician considers that the patient is gaining clinical benefit from the inclusion of Dilaterol into their standard treatment regimen. If there is clinical deterioration of the pulmonary status, additional anti-pseudomonal therapy should be considered. Data from clinical studies indicated that a microbiological report of in vitro drug resistance did not preclude necessarily, a clinical benefit for the patient.

Special populations

Elderly patients (> 65 years)

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

Patients with renal impairment

Patients with hepatic impairment

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

Patients after organ transplantation

Adequate data do not exist for the use of Dilaterol in patients after organ transplantation.

Paediatric population

The safety and efficacy of tobromycin in children aged less than 6 years have not yet been established.

Method of administration

The entire contents of one ampoule should be emptied into the nebuliser and administered by inhalation over an approximate 15-minute period using a commercially available hand-held PARI LC PLUS reusable Nebuliser with a suitable compressor. The compressor should deliver a flow rate of 4 - 6 L/min and/or a back pressure of 110 - 217 kPa when attached to the nebuliser. It is important that the manufacturer's instruction for care and use of the Nebuliser and Compressor are followed.

Dilaterol is inhaled by the patient in the sitting or a standing upright posture and who is breathing normally through the mouthpiece of the Nebuliser. The use of a nose clip may help the patient breathe through the mouth. When taking Dilaterol, it is important that the patient continues their standard regimen of chest physiotherapy. The use of appropriate bronchodilators should continue as deemed necessary. When patients are taking several different respiratory therapies it is recommended that they are taken in the following order: bronchodilator, chest physiotherapy, other inhaled medicinal products and, finally, Dilaterol.

Maximum tolerated daily dose

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

General warnings

Dilaterol 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 Dilaterol concentrations

Serum Dilaterol concentrations should be monitored in patients with known or suspected auditory or renal dysfunction. If oto- or nephrotoxicity occurs in a patient receiving Dilaterol, Dilaterol should be discontinued until serum concentrations fall below 2 µg/ml.

Serum concentrations of Dilaterol 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.

Serum concentrations of Dilaterol should only be measured in blood samples obtained by venipuncture. Finger-prick blood sampling is not recommended as it is not a validated method and it has been observed that contamination of the skin of the fingers from the preparation and nebulisation may lead to falsely increased serum levels of Dilaterol. Furthermore, the contamination cannot be avoided by hand washing before testing.

Bronchospasm

Bronchospasm can occur with nebulised Dilaterol, as is the case with other inhaled medicinal products. The first dose of Dilaterol should be administered under supervision, using a pre-nebulisation bronchodilator if it is part of the patient's current regimen. FEV₁ should be measured before and after nebulisation. If there is evidence of therapy-induced bronchospasm in a patient not receiving a bronchodilator, then the test should be repeated on another occasion using a bronchodilator. If bronchospasm occurs in the presence of a bronchodilator, then an allergic response may be indicative and Dilaterol should be discontinued. Bronchospasm should be treated as medically appropriate.

Neuromuscular disorders

Dilaterol should be used with extreme caution in patients with neuromuscular disorders such as Parkinsonism and conditions characterised by myasthenia, including myasthenia gravis, as aminoglycosides may aggravate muscular weakness, because of 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 Dilaterol.

The product should be used with caution in patients with known or suspected renal dysfunction and serum Dilaterol concentrations 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 six complete cycles of Dilaterol therapy (180 days of nebulised aminoglycoside therapy). If there is any evidence of nephrotoxicity, all Dilaterol therapy should be discontinued until trough serum Dilaterol concentrations fall below 2 µg/mL. Dilaterol may then be resumed at the physician's discretion. Patients receiving concomitant parenteral aminoglycoside therapy should be monitored as clinically appropriate taking into account the risk of cumulative toxicity.

Ototoxicity

Ototoxicity is manifested as both auditory and vestibular toxicity and has been reported with parenteral aminoglycosides. Audiotoxicity, as measured by complaints of hearing loss or by audiometric evaluation did not occur with Dilaterol treatment in controlled clinical studies. In open-label studies and post-marketing experience, some patients with a previous or concomitant use of intravenous aminoglycosides experience hearing loss. Patients with hearing loss frequently reported tinnitus. Vestibular toxicity is manifested by vertigo, ataxia or dizziness. Physicians should consider the potential for aminoglycosides to cause cochlear or vestibular toxicity and to carry out appropriate assessments of auditory function during Dilaterol treatment. In patients with a predisposing risk of ototoxicity due to previous, systemic aminoglycoside therapy, it may be necessary to consider audiological assessment prior to starting Dilaterol treatment. Furthermore, the onset of tinnitus, which is a symptom of ototoxicity, warrants caution. If a patient reports occurrence of tinnitus or hearing loss, the physician should refer the patient for audiological assessment. Patients receiving concomitant parenteral aminoglycoside therapy should be appropriately monitored taking into account the risk of toxicity.

Caution should be exercised when prescribing Dilaterol 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.

Haemoptysis

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

Some patients receiving Dilaterol show an increase in aminoglycoside Minimum Inhibitory Concentrations of P. aeruginosa isolates tested. There is a theoretical risk that patients being treated with nebulised Dilaterol may develop P. aeruginosa isolates resistant to intravenous Dilaterol.

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

In controlled clinical trials, voice alteration and tinnitus were the only undesirable effects reported in significantly more patients treated with Dilaterol than in the control group; (13% Dilaterol vs 7% control) and (3% Dilaterol vs 0% control), respectively. The episodes of tinnitus were transient and resolved without discontinuation of Dilaterol therapy; the incidence of tinnitus was not associated with permanent loss of hearing on audiogram testing. The risk of tinnitus did not increase with repeated cycles of exposure to Dilaterol.

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

Frequency estimate: 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).

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 4.3, 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..

Inhalation of Dilaterol results in low systemic bioavailability. Symptoms of aerosol overdose may include severe hoarseness.

In the event of accidental ingestion of Tymbrineb Nebuliser Solution, toxicity is unlikely to occur and Dilaterol is poorly absorbed from the gastrointestinal tract.

In the case of inadvertent intravenous administration of Tymbrineb Nebuliser Solution, signs and symptoms of parenteral Dilaterol overdose may occur, which include dizziness, tinnitus, vertigo, loss of hearing, respiratory distress and/or neuromuscular blockade and renal impairment.

In the event of acute toxicity, treatment includes immediate withdrawal of Dilaterol and baseline renal function testing. Serum Dilaterol concentrations may be helpful in monitoring overdose. In the case of overdosage, the possibility of drug interactions with alterations in the elimination of Dilaterol or other medicinal products should be considered.

Pharmacotherapeutic group: Aminoglycoside Antibacterials,

ATC code: JO1GB01

Mechanism of action

Dilaterol is an aminoglycoside antibiotic produced by Streptomyces tenebrarius. Its mechanism of action is primarily by disrupting protein synthesis leading to altered cell membrane permeability, progressive disruption of the cell envelope and eventual cell death. It is bactericidal at concentrations equal to or slightly greater than inhibitory concentrations.

Mechanism of resistance

Resistance to Dilaterol can occur via several mechanisms including: alterations of the ribosomal subunit within the bacterial cell, interference with the transport of Dilaterol into the cell and inactivation of Dilaterol by several enzymes (for example, adenylylating, phosphorylating and acetylating enzymes). Cross resistance to other aminoglycosides may also occur.

Breakpoints

The breakpoints, as mentioned below, are based on systemic Dilaterol use and might not be applicable to nebulised Dilaterol. In accordance with CPMP/EWP/558/95 rev.1, the following Minimum Inhibitory Concentration (MIC) breakpoints are defined for Dilaterol by EUCAST (European Committee on Antimicrobial Susceptibility Testing Version 1.1 2010).

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, active advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

The organisms associated with pulmonary infections in CF that may be expected to respond to inhaled Dilaterol are as follows:

Information from clinical studies

The local biological activity of nebulised aminoglycosides is inhibited by the sputum from patients with CF. Therefore, the sputum concentrations of aerosolised Dilaterol needs to be around 10 and 25 fold, above the MIC, respectively, for P. aeruginosa growth suppression and bactericidal activity. In controlled clinical trials, 97% of patients receiving inhaled Dilaterol achieved sputum concentrations 10 fold the highest P. aeruginosa MIC cultured from the patient and 95% of patients receiving inhaled Dilaterol 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.

In 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 Dilaterol. However, clinical studies showed that a microbiological report indicating in vitro drug resistance did not necessarily preclude a clinical benefit for the patient.

Most patients with P. aeruginosa isolates with Dilaterol MICs <128 µg/ml at baseline showed improved lung function after treatment with inhaled Dilaterol. Patients with a P. aeruginosa isolate with a MIC >128 µg/ml at baseline are less likely to show a clinical response. However, seven of 13 patients (54%) in the placebo-controlled studies who acquired isolates with MICs >128 µg/ml while using inhaled Dilaterol had improved lung function.

Over the entire 96 week duration of the extension studies, the Dilaterol MIC50 for P. aeruginosa increased from 1 to 2 µg/ml and the MIC90 increased from 8 to 32 µg/ml.

In clinical studies, inhaled Dilaterol showed a small but clear increase in Dilaterol, amikacin and gentamycin MIC for P. aeruginosa isolates tested. Each additional six months of treatment resulted in incremental increases similar in magnitude to that observed in the six months of controlled studies. The most prevalent aminoglycoside resistance mechanism seen in P. aeruginosa isolated from chronically infected CF patients is impermeability, defined by a general lack of susceptibility to all aminoglycosides. P. aeruginosa isolated from CF patients has also been shown to exhibit adaptive aminoglycoside resistance that can be characterised by a reversion to susceptibility when the antibiotic is removed.

Other information

There is no evidence that patients treated for up to 18 months with inhaled Dilaterol were at greater risk for acquiring B. cepacia, S. matlophilia or A. xylosoxidans, than would be expected in patients not treated with Dilaterol. Aspergillus species were more frequently recovered from the sputum of patients receiving Dilaterol; however, clinical sequelae such as Allergic Bronchopulmonary Aspergillosis was rarely reported and with similar frequency as in the control group.

There are insufficient clinical safety and efficacy data in children < 6 years of age.

In an open-label uncontrolled study, 88 patients with CF (37 patients between 6 months and 6 years, 41 patients between 6 and 18 years of age and 10 patients above 18 years of age) with early (non-chronic) P. aeruginosa infection were treated for 28 days with Dilaterol. After 28 days, patients were randomised 1:1 to either stop (n=45) or to receive a further 28 days treatment (n=43).

Primary outcome was the median time to recurrence of P. aeruginosa (any strain) which was 26.1 and 25.8 months for the 28-day and 56-day groups, respectively. It was found that 93 % and 92 % of the patients were free of P. aeruginosa infection 1 month after the end of treatment in the 28-day and 56-day groups, respectively. The use of Dilaterol with a dosing regimen longer than 28 days continuous treatment is not approved.

Clinical efficacy

Two identically designed, double-blind, randomised, placebo-controlled, parallel group, 24-week clinical studies (Study 1 and Study 2) were conducted in cystic fibrosis patients with P. aeruginosa to support original registration which took place in 1999. These studies enrolled 520 subjects who had a baseline FEV1 of between 25% and 75% of their predicted normal value. Patients who were less than six years of age, or who had a baseline creatinine of > 2 mg/dl or who had Burkholderia cepacia isolated from sputum were excluded. In these clinical studies, 258 patients received Dilaterol therapy on an outpatient basis using a hand-held PARI LC PLUS™ Reusable Nebuliser with a DeVilbiss® Pulmo-Aide® compressor.

In each study, Dilaterol-treated patients experienced significant improvement in pulmonary function and significant reduction in the number of P. aeruginosa colony forming units (CFUs) in sputum during the on-drug periods. The mean FEV1 remained above baseline in the 28-day off-drug periods, although it reversed somewhat on most occasions. Sputum bacterial density returned to baseline during the offdrug periods. Reductions in sputum bacterial density were smaller in each successive cycle.

Patients treated with Dilaterol experienced fewer hospitalisation days and required fewer days of parenteral anti-pseudomonal antibiotics on average, compared with placebo patients.

In open label extensions to the studies 1 and 2, there were 396 patients of the 464 who completed either of the two 24 week double blind studies. In total, 313, 264 and 120 patients completed treatment with Dilaterol for 48, 72 and 96 weeks respectively. The rate of lung function decline was significantly lower following initiation of Dilaterol therapy than that observed among patients receiving placebo during the double blind randomised treatment period. The estimated slope in the regression model of lung function decline was -6.52% during the blinded placebo treatment and -2.53% during Dilaterol treatment.

Absorption

Dilaterol is a cationic polar molecule that does not readily cross epithelial membrances. The systemic exposure to Dilaterol after inhalation is expected to result from pulmonary absorption of the dose fraction delivered to the lungs as Dilaterol is not absorbed to any appreciable extent when administered via the oral route. The bioavailability of Dilaterol may vary because of individual differences in nebuliser performance and airway pathology.

Sputum concentrations: Ten minutes after the first inhalation of Dilaterol 300 mg, the average sputum concentration of Dilaterol was 1,237 µg/g (range: 35 to 7,414 µg/g). There is no accumulation of Dilaterol in the sputum; after 20 weeks of therapy with the Dilaterol regimen, the average sputum concentration of Dilaterol 10 minutes after inhalation was 1,154 µg/g (range: 39 to 8,085 µg/g). High variability of sputum Dilaterol concentrations was observed. Two hours following inhalation, sputum concentration declined to approximately 14% of the 10 minute measurement.

Serum concentrations: The median serum concentration of Dilaterol, one hour after inhalation, was 0.95 µg/ml (range: below the limit of quantitation to 3.62 µg/ml). After 20 weeks of therapy, the median serum Dilaterol concentration, one hour after dosing, was 1.05 µg/ml (range: below the limit of quantitation to 3.41 µg/ml). For comparison, the peak concentrations after intravenous or intramuscular administration of a single Dilaterol dose of 1.5 to 2 mg/kg typically range from 4 to 12 µg/ml.

Distribution

Dilaterol remains concentrated in the airways following administration. Less than 10% of Dilaterol is bound to plasma proteins.

Biotransformation

Dilaterol is not metabolised and is primarily excreted unchanged in the urine.

Elimination

The elimination of Dilaterol administered via inhalation has not been studied.

Systemically absorbed Dilaterol is eliminated principally by glomerular filtration of the unchanged compound. The apparent terminal half-life of Dilaterol in serum after inhalation of a 300 mg single dose of Dilaterol was 3 hours in cystic fibrosis patients.

Renal function is expected to affect the exposure to Dilaterol, however data are not available as patients with serum creatinine 2 mg/dl (176,8 µmol/l) or more or blood urea nitrogen (BUN) 40 mg/dl or more were not included in clinical studies.

Unabsorbed Dilaterol is probably eliminated in expectorated sputum.

Pre-clinical data reveal that the main hazards for humans, based on safety pharmacology, repeated dose toxicity, genotoxicity or reproductive toxicity, are nephrotoxicity and ototoxicity. In repeat-dose studies, toxicity is targeted at the kidneys and vestibular/cochlear functions. Toxicity is seen at much higher systemic concentrations than are achievable by inhalation at the recommended clinical dose.

Carcinogenicity studies with inhaled Dilaterol do not increase the incidence of any variety of tumour. Dilaterol showed no genetic potential in a battery of genotoxicity tests.

No reproductive toxicity studies have been performed with nebulised Dilaterol. Subcutaneous administration of Dilaterol 100 mg/kg/day in rats and the maximum tolerated dose of 20 mg/kg/day in rabbits, during organogenesis, was not teratogenic. Teratogenicity could not be assessed at higher parenteral doses in rabbits due to maternal toxicity and abortion. Ototoxicity was not evaluated in offspring during nonclinical reproduction toxicity studies with Dilaterol.

Based on available data from animals, a risk of toxicity (e.g. ototoxicity) at prenatal exposures cannot be excluded.

Subcutaneous administration of up to 100 mg/kg of Dilaterol did not affect mating behaviour or cause impairment of fertility in male or female rats.

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

This medicinal product is a sterile, non-pyrogenic, aqueous preparation for single-use only. As it is preservative-free, the contents of the whole ampoule should be used immediately after opening and any unused solution discarded. Opened ampoules should never be stored for re-use.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.