Adverse reactions specifically associated with overdose of Тоби Подхалер have not been identified. The maximum tolerated daily dose of Тоби Подхалер has not been established. Tobramycin serum concentrations may be helpful in monitoring overdosage. In case of signs of acute toxicity, immediate withdrawal of Тоби Подхалер and testing of renal function are recommended. In the event of accidental oral ingestion of Тоби Подхалер capsules, toxicity is unlikely as tobramycin is poorly absorbed from an intact gastrointestinal tract. Haemodialysis may be helpful in removing tobramycin from the body.
Inhalation of Тоби Подхалер 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 Тоби Подхалер is poorly absorbed from the gastrointestinal tract.
In the case of inadvertent intravenous administration of Tymbrineb Nebuliser Solution, signs and symptoms of parenteral Тоби Подхалер 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 Тоби Подхалер and baseline renal function testing. Serum Тоби Подхалер concentrations may be helpful in monitoring overdose. In the case of overdosage, the possibility of drug interactions with alterations in the elimination of Тоби Подхалер or other medicinal products should be considered.
Not applicable
In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal product.
Summary of the safety profile
The most commonly reported adverse reactions in the main safety, active-controlled clinical study with Тоби Подхалер 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 Тоби Подхалер, the adverse reactions for which reported frequency was higher with Тоби Подхалер than with placebo were pharyngolaryngeal pain, dysgeusia and dysphonia.
The vast majority of adverse reactions reported with Тоби Подхалер 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 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); not known: frequency 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, connective tissue and bone disorders | |
| Musculoskeletal chest pain | Common |
| 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 Тоби Подхалер 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 Тоби Подхалер 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: mhra.gsi.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
In controlled clinical trials, voice alteration and tinnitus were the only undesirable effects reported in significantly more patients treated with Тоби Подхалер than in the control group; (13% Тоби Подхалер vs 7% control) and (3% Тоби Подхалер vs 0% control), respectively. The episodes of tinnitus were transient and resolved without discontinuation of Тоби Подхалер 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 Тоби Подхалер.
Additional undesirable effects, some of which are common sequelae of the underlying disease, but where a causal relationship to Тоби Подхалер 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).
| MedDra - system organ class | Frequency and Symptom |
| Infections and infestations | Rare: - Laryngitis Very rare:- Oral candidiasis, fungal infection |
| Blood and lymphatic system disorders | Very rare: Lymphadenopathy |
| Immune system disorders | Very rare: Hypersensitivity |
| Metabolism and nutrition disorders | Rare: Anorexia |
| Nervous system disorders | Rare: - Dizziness, headache, aphonia Very rare: - Somnolence |
| Ear and labyrinth disorders | Rare: - Tinnitus, hearing loss Very rare: - Ear disorder, ear pain |
| Respiratory, thoracic and mediastinal disorders | Uncommon: - Dysphonia, dyspnoea, cough, pharyngitis Rare: - Bronchospasm, chest discomfort, productive cough, lung disorder, haemoptysis, epistaxis, rhinitis, asthma Very rare: - Hyperventilation, hypoxia, sinusitis |
| Gastrointestinal disorders | Rare: - Dysgeusia, nausea, mouth ulceration, vomiting Very rare: - Diarrhoea, abdominal pain |
| Skin and subcutaneous tissue disorders | Rare: Rash Very rare: - Urticaria, pruritus |
| Musculoskeletal and connective tissue disorders | Rare: Back pain |
| General disorders and administration site conditions | Rare: Asthenia, pyrexia, chest pain, pain Very rare: Malaise |
| Investigations | Rare: Pulmonary function test decreased |
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..
Non-clinical data reveal that the main hazard for humans, based on studies of safety pharmacology, repeated dose toxicity, genotoxicity, or toxicity to reproduction, consists of renal toxicity and ototoxicity. In general, toxicity is seen at higher systemic tobramycin levels than are achievable by inhalation at the recommended clinical dose.
Carcinogenicity studies with inhaled tobramycin do not increase the incidence of any variety of tumour. Tobramycin showed no genotoxic potential in a battery of genotoxicity tests.
No reproduction toxicology studies have been conducted with tobramycin administered by inhalation. However, subcutaneous administration of tobramycin during organogenesis was not teratogenic nor embryotoxic. Severely maternally toxic doses to female rabbits (i.e. nephrotoxicity) lead to spontaneous abortions and death. Based on available data from animals a risk of toxicity (e.g. ototoxicity) at prenatal exposure levels cannot be excluded.
Subcutaneous administration of tobramycin did not affect mating behaviour or cause impairment of fertility in male or female rats.
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 Тоби Подхалер do not increase the incidence of any variety of tumour. Тоби Подхалер showed no genetic potential in a battery of genotoxicity tests.
No reproductive toxicity studies have been performed with nebulised Тоби Подхалер. Subcutaneous administration of Тоби Подхалер 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 Тоби Подхалер.
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 Тоби Подхалер did not affect mating behaviour or cause impairment of fertility in male or female rats.
Тоби Подхалер 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.
1 regarding data in different age groups.
Consideration should be given to official guidance on the appropriate use of antibacterial agents.
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.
Pharmacotherapeutic group: Antibacterials for systemic use, Aminoglycoside antibacterials, ATC Code: J01GB01
Mechanism of action
Tobramycin is an aminoglycoside antibiotic produced by Streptomyces tenebrarius. It acts 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.
Breakpoints
Established susceptibility breakpoints for parenteral administration of tobramycin are inappropriate in the aerosolised administration of the medicinal product.
Sputum from cystic fibrosis exhibits an inhibitory action on the local biological activity of inhaled aminoglycosides. This necessitates sputum concentrations of tobramycin after inhalation to be about ten-fold above the minimum inhibitory concentration (MIC) or higher for P. aeruginosa suppression. In the active-controlled study, at least 89% of patients had P. aeruginosa isolates with MICs at least 15 times lower than mean post-dose sputum concentration, both at baseline and at the end of the third active treatment cycle.
Susceptibility
In the absence of conventional susceptibility breakpoints for the inhaled route of administration, caution must be exercised in defining organisms as susceptible or insusceptible to inhaled tobramycin.
The clinical significance of changes in MICs of tobramycin for P. aeruginosa has not been clearly established in the treatment of cystic fibrosis patients. Clinical studies with inhaled tobramycin solution (TOBI) have shown a small increase in tobramycin, amikacin and gentamicin Minimum Inhibitory Concentrations for P. aeruginosa isolates tested. In the open label extensions, each additional 6 months of treatment resulted in incremental increases similar in magnitude to that observed in the 6 months of placebo-controlled studies.
Resistance to tobramycin involves different mechanisms. The main resistance mechanisms are drug efflux and drug inactivation by modifying enzymes. The unique characteristics of chronic P. aeruginosa infections in CF patients, such as anaerobic conditions and high frequency of genetic mutations, may also be important factors for reduced susceptibility of P. aeruginosa in CF patients.
Based upon in vitro data and/or clinical trial experience, the organisms associated with pulmonary infections in CF may be expected to respond to Тоби Подхалер therapy as follows:
| Susceptible | Pseudomonas aeruginosa Haemophilus influenzae Staphylococcus aureus |
| Insusceptible | Burkholderia cepacia Stenotrophomonas maltophilia Alcaligenes xylosoxidans |
Clinical experience
The Тоби Подхалер Phase III clinical development programme consisted of two studies and 612 treated patients with a clinical diagnosis of CF, confirmed by quantitative pilocarpine iontophoresis sweat chloride test or well-characterised disease causing mutations in each cystic fibrosis transmembrane regulator (CFTR) gene, or abnormal nasal transepithelial potential difference characteristic of CF.
In the placebo controlled study, patients were aged 6 - ≤22 years with an FEV1 at screening of between 25% and 84% of predicted normal values for their age, sex and height based upon Knudson criteria. In the active controlled studies, all patients were aged >6years old (range 6-66 years) with an FEV1 % predicted at screening of between 24% and 76%. In addition, all patients were infected with P. aeruginosa as demonstrated by a positive sputum or throat culture (or bronchoalveolar lavage) within 6 months prior to screening, and also in a sputum culture taken at the screening visit.
In a randomised, double-blind, placebo-controlled, multicentre study, Тоби Подхалер 112 mg (4 x 28 mg capsules) was administered twice daily, for three cycles of 28 days on-treatment and 28 days off-treatment (a total treatment period of 24 weeks). Patients who were randomised to the placebo treatment group received placebo during the first treatment cycle and Тоби Подхалер in the subsequent two cycles. Patients in this study had no exposure to inhaled tobramycin for at least 4 months prior to study start.
Тоби Подхалер significantly improved lung function compared with placebo, as shown by the relative increase in percent predicted FEV1 of about 13% after 28 days of treatment. The improvements in lung function achieved during the first treatment cycle were maintained during the two subsequent cycles of treatment with Тоби Подхалер.
When patients in the placebo treatment group were switched from placebo to Тоби Подхалер at the start of the second treatment cycle, they experienced a similar improvement from baseline in percent predicted FEV1. Treatment with Тоби Подхалер for 28 days resulted in a statistically significant reduction in P. aeruginosa sputum density (mean difference with placebo about 2.70 log10 in colony forming units/CFUs).
In a second open-label, multicentre study, patients received treatment with either Тоби Подхалер (112 mg) or tobramycin 300 mg/5 ml nebuliser solution (TOBI), administered twice daily for three cycles. A majority of the patients were tobramycin-experienced adults with chronic pulmonary P. aeruginosa infection.
Treatment with both Тоби Подхалер and tobramycin 300 mg/5 ml nebuliser solution (TOBI) resulted in relative increases from baseline to day 28 of the third treatment cycle in percent predicted FEV1 of 5.8% and 4.7%, respectively. The improvement in percent predicted FEV1 was numerically greater in the Тоби Подхалер treatment group and was statistically non-inferior to TOBI nebuliser solution. Although the magnitude of improvements in lung function was smaller in this study, this is explained by the previous exposure of this patient population to treatment with inhaled tobramycin. Over half of the patients in both the Тоби Подхалер and TOBI nebuliser solution treatment groups received new (additional) anti-pseudomonal antibiotics (64.9% and 54.5% respectively, the difference consisting mainly of oral ciprofloxacin use). The proportions of patients requiring hospitalisation for respiratory events were 24.4% with Тоби Подхалер and 22.0% with TOBI nebuliser solution.
A difference in FEV1 response by age was noted. In the patients aged <20 years the increase from baseline percent predicted FEV1 was larger: 11.3% for Тоби Подхалер and 6.9% for the nebuliser solution after 3 cycles. A numerically lower response in patients aged >20 years was observed: the change from baseline FEV1 observed in the patients aged >20 years was smaller (0.3% with Тоби Подхалер and 0.9% with TOBI nebuliser solution).
Furthermore, an improvement of 6% in percent predicted FEV1 was obtained in about 30% versus 36% of the adult patients in the Тоби Подхалер and TOBI nebuliser solution group respectively.
Treatment with Тоби Подхалер for 28 days resulted in a statistically significant reduction in P. aeruginosa sputum density (-1.61 log10 CFUs), as did the nebuliser solution (-0.77 log10 CFUs). Suppression of sputum P. aeruginosa density was similar across age groups in both arms. In both studies, there was a trend for a recovery of P. aeruginosa density after the 28 days off-treatment period, which was reversed after a further 28 days on-treatment.
In the active-controlled study, administration of a Тоби Подхалер dose was faster with a mean difference of approximately 14 minutes (6 minutes vs. 20 minutes with the nebuliser solution). Patient-reported convenience and overall treatment satisfaction (as collected through a patient-reported outcomes questionnaire) were consistently higher with Тоби Подхалер compared with tobramycin nebuliser solution in each cycle.
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with Тоби Подхалер in one or more subsets of the paediatric population in treatment of pseudomonas aeruginosa pulmonary infection/colonisation in patients with cystic fibrosis (see section 4.2 for information on paediatric use).
Pharmacotherapeutic group: Aminoglycoside Antibacterials,
ATC code: JO1GB01
Mechanism of action
Тоби Подхалер 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 Тоби Подхалер can occur via several mechanisms including: alterations of the ribosomal subunit within the bacterial cell, interference with the transport of Тоби Подхалер into the cell and inactivation of Тоби Подхалер 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 Тоби Подхалер use and might not be applicable to nebulised Тоби Подхалер. In accordance with CPMP/EWP/558/95 rev.1, the following Minimum Inhibitory Concentration (MIC) breakpoints are defined for Тоби Подхалер by EUCAST (European Committee on Antimicrobial Susceptibility Testing Version 1.1 2010).
| Enterobacteriaceae | S ≤2 mg/L, R >4 mg/L |
| Pseudomonas spp. | S ≤4 mg/L, R >4 mg/L |
| Acinetobacter spp. | S ≤4 mg/L, R >4 mg/L |
| Staphylococcus spp. | S ≤1 mg/L, R >1 mg/L |
| Non-species related | S ≤2 mg/L, R >4 mg/L |
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 Тоби Подхалер are as follows:
| Susceptible | Pseudomonas aeruginosa Haemophilus influenzae Staphylococcus aureus |
| Insusceptible | Burkholderia cepacia Stentrophomonas maltophilia Alcaligenes xylosoxidans |
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 Тоби Подхалер 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 Тоби Подхалер achieved sputum concentrations 10 fold the highest P. aeruginosa MIC cultured from the patient and 95% of patients receiving inhaled Тоби Подхалер 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 Тоби Подхалер. 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 Тоби Подхалер MICs <128 µg/ml at baseline showed improved lung function after treatment with inhaled Тоби Подхалер. 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 Тоби Подхалер had improved lung function.
Over the entire 96 week duration of the extension studies, the Тоби Подхалер 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 Тоби Подхалер showed a small but clear increase in Тоби Подхалер, 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 Тоби Подхалер were at greater risk for acquiring B. cepacia, S. matlophilia or A. xylosoxidans, than would be expected in patients not treated with Тоби Подхалер. Aspergillus species were more frequently recovered from the sputum of patients receiving Тоби Подхалер; 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 Тоби Подхалер. 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 Тоби Подхалер 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 Тоби Подхалер therapy on an outpatient basis using a hand-held PARI LC PLUSâ„¢ Reusable Nebuliser with a DeVilbiss® Pulmo-Aide® compressor.
In each study, Тоби Подхалер-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 Тоби Подхалер 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 Тоби Подхалер for 48, 72 and 96 weeks respectively. The rate of lung function decline was significantly lower following initiation of Тоби Подхалер 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 Тоби Подхалер treatment.
Absorption
The systemic exposure to tobramycin after inhalation of Тоби Подхалер is expected to be primarily from the inhaled portion of the medicinal product as tobramycin is not absorbed to any appreciable extent when administered via the oral route.
Serum concentrations
After inhalation of a 112 mg single dose (4 x 28 mg capsules) of Тоби Подхалер in cystic fibrosis patients, the maximum serum concentration (Cmax) of tobramycin was 1.02 ± 0.53 μg/ml (mean ± SD) and the median time to reach the peak concentration (Tmax) was one hour. In comparison, after inhalation of a single dose of tobramycin 300 mg/5 ml nebuliser solution (TOBI), Cmax was 1.04 ± 0.58 µg/ml and median Tmax was one hour. The extent of systemic exposure (AUC) was also similar for the 112 mg Тоби Подхалер dose and the 300 mg tobramycin nebuliser solution dose. At the end of a 4-week dosing cycle of Тоби Подхалер (112 mg twice daily), maximum serum concentration of tobramycin 1 hour after dosing was 1.99 ± 0.59 µg/ml.
Sputum concentrations
After inhalation of a 112 mg single dose (4 x 28 mg capsules) of Тоби Подхалер in cystic fibrosis patients, sputum Cmax of tobramycin was 1047 ± 1080 µg/g (mean ± SD). In comparison, after inhalation of a single 300 mg dose of tobramycin nebuliser solution (TOBI), sputum Cmax was 737.3 ± 1028.4 µg/g. The variability in pharmacokinetic parameters was higher in sputum as compared to serum.
Distribution
A population pharmacokinetic analysis for Тоби Подхалер in cystic fibrosis patients estimated the apparent volume of distribution of tobramycin in the central compartment to be 84.1 litres for a typical CF patient. While the volume was shown to vary with body mass index (BMI) and lung function (as FEV1% predicted), model-based simulations showed that peak (Cmax) and trough (Ctrough) concentrations were not impacted markedly with changes in BMI or lung function.
Biotransformation
Tobramycin is not metabolised and is primarily excreted unchanged in the urine.
Elimination
Tobramycin is eliminated from the systemic circulation primarily by glomerular filtration of the unchanged compound. The apparent terminal half-life of tobramycin in serum after inhalation of a 112 mg single dose of Тоби Подхалер was approximately 3 hours in cystic fibrosis patients and consistent with the half-life of tobramycin after inhalation of tobramycin 300 mg/5 ml nebuliser solution (TOBI).
A population pharmacokinetic analysis for Тоби Подхалер in cystic fibrosis patients aged 6 to 66 years estimated the apparent serum clearance of tobramycin to be 14 litres/h. This analysis did not show gender or age-related pharmacokinetic differences
Absorption
Тоби Подхалер is a cationic polar molecule that does not readily cross epithelial membrances. The systemic exposure to Тоби Подхалер after inhalation is expected to result from pulmonary absorption of the dose fraction delivered to the lungs as Тоби Подхалер is not absorbed to any appreciable extent when administered via the oral route. The bioavailability of Тоби Подхалер may vary because of individual differences in nebuliser performance and airway pathology.
Sputum concentrations: Ten minutes after the first inhalation of Тоби Подхалер 300 mg, the average sputum concentration of Тоби Подхалер was 1,237 µg/g (range: 35 to 7,414 µg/g). There is no accumulation of Тоби Подхалер in the sputum; after 20 weeks of therapy with the Тоби Подхалер regimen, the average sputum concentration of Тоби Подхалер 10 minutes after inhalation was 1,154 µg/g (range: 39 to 8,085 µg/g). High variability of sputum Тоби Подхалер 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 Тоби Подхалер, 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 Тоби Подхалер 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 Тоби Подхалер dose of 1.5 to 2 mg/kg typically range from 4 to 12 µg/ml.
Distribution
Тоби Подхалер remains concentrated in the airways following administration. Less than 10% of Тоби Подхалер is bound to plasma proteins.
Biotransformation
Тоби Подхалер is not metabolised and is primarily excreted unchanged in the urine.
Elimination
The elimination of Тоби Подхалер administered via inhalation has not been studied.
Systemically absorbed Тоби Подхалер is eliminated principally by glomerular filtration of the unchanged compound. The apparent terminal half-life of Тоби Подхалер in serum after inhalation of a 300 mg single dose of Тоби Подхалер was 3 hours in cystic fibrosis patients.
Renal function is expected to affect the exposure to Тоби Подхалер, 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 Тоби Подхалер is probably eliminated in expectorated sputum.
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 Тоби Подхалер clinical studies. Caution should be exercised when prescribing Тоби Подхалер 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 Тоби Подхалер therapy.
If a patient reports tinnitus or hearing loss during Тоби Подхалер 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 Тоби Подхалер clinical studies. Caution should be exercised when prescribing Тоби Подхалер 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 Тоби Подхалер therapy.
“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 Тоби Подхалер, 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 Тоби Подхалер in clinical studies. Bronchospasm should be treated as medically appropriate.
The first dose of Тоби Подхалер 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 Тоби Подхалер.
If there is evidence of therapy-induced bronchospasm, the physician should carefully evaluate whether the benefits of continued use of Тоби Подхалер outweigh the risks to the patient. If an allergic response is suspected, Тоби Подхалер should be discontinued.
Cough
Cough was reported with use of Тоби Подхалер in clinical studies. Based on clinical trial data the inhalation powder Тоби Подхалер 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 Тоби Подхалер compared with older subjects.
If there is evidence of continued therapy-induced cough with Тоби Подхалер, 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 Тоби Подхалер in these patients. This should be taken into account before prescribing Тоби Подхалер, considering the inhalation powder Тоби Подхалер was associated with a higher rate of cough (see above). The use of Тоби Подхалер 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 Тоби Подхалер therapy.
See also “Monitoring of serum tobramycin concentrations†above.
Caution should be exercised when prescribing Тоби Подхалер 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 Тоби Подхалер 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 Тоби Подхалер may develop P. aeruginosa isolates resistant to intravenous tobramycin over time. 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 Тоби Подхалер 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.
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 Тоби Подхалер.
Safety and efficacy have not been studied in patients with forced expiratory volume in 1 second (FEV1) <25% or >75% predicted, or patients colonised with Burkholderia cepacia.
General warnings
Тоби Подхалер 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 Тоби Подхалер concentrations
Serum Тоби Подхалер concentrations should be monitored in patients with known or suspected auditory or renal dysfunction. If oto- or nephrotoxicity occurs in a patient receiving Тоби Подхалер, Тоби Подхалер should be discontinued until serum concentrations fall below 2 µg/ml.
Serum concentrations of Тоби Подхалер 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 Тоби Подхалер 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 Тоби Подхалер. Furthermore, the contamination cannot be avoided by hand washing before testing.
Bronchospasm
Bronchospasm can occur with nebulised Тоби Подхалер, as is the case with other inhaled medicinal products. The first dose of Тоби Подхалер 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 Тоби Подхалер should be discontinued. Bronchospasm should be treated as medically appropriate.
Neuromuscular disorders
Тоби Подхалер 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 Тоби Подхалер.
The product should be used with caution in patients with known or suspected renal dysfunction and serum Тоби Подхалер 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 Тоби Подхалер therapy (180 days of nebulised aminoglycoside therapy). If there is any evidence of nephrotoxicity, all Тоби Подхалер therapy should be discontinued until trough serum Тоби Подхалер concentrations fall below 2 µg/mL. Тоби Подхалер 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 Тоби Подхалер 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 Тоби Подхалер 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 Тоби Подхалер 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 Тоби Подхалер 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 Тоби Подхалер 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 Тоби Подхалер show an increase in aminoglycoside Minimum Inhibitory Concentrations of P. aeruginosa isolates tested. There is a theoretical risk that patients being treated with nebulised Тоби Подхалер may develop P. aeruginosa isolates resistant to intravenous Тоби Подхалер.
Тоби Подхалер has no or negligible influence on the ability to drive and use machines.
Тоби Подхалер has negligible influence on the ability to drive and use machines.
Posology
The dose of Тоби Подхалер 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. Тоби Подхалер 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 Тоби Подхалер should be continued on a cyclical basis for as long as the physician considers the patient is gaining clinical benefit from the treatment with Тоби Подхалер.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 Тоби Подхалер. Caution should be exercised when prescribing Тоби Подхалер to patients with known or suspected renal dysfunction.
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 Тоби Подхалер in patients after organ transplantation. No recommendation for or against dose adjustment can be made for patients after organ transplantation.
Paediatric patients
The safety and efficacy of Тоби Подхалер in children aged under 6 years have not been established. No data are available.
Method of administration
Inhalation use.
). It must not be administered by any other route or using any other inhaler.
Caregivers should provide assistance to children starting Тоби Подхалер 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.
Тоби Подхалер capsules must not be swallowed. Each Тоби Подхалер 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 Тоби Подхалер is taken last.
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 Тоби Подхалер 300 mg twice daily.
Tymbrineb Dosing Regimen in Controlled Clinical Studies
| Cycle 1 | Cycle 2 | Cycle 3 | |||
| 28 days | 28 days | 28 days | 28 days | 28 days | 28 days |
| Tymbrineb 300 mg twice daily plus standard care | Standard care only | Tymbrineb 300 mg twice daily plus standard care | Standard care only | Tymbrineb 300 mg twice daily plus standard care | Standard care only |
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. Тоби Подхалер 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 Тоби Подхалер 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
2.Patients with hepatic impairment
No studies have been performed on patients with hepatic impairment. As Тоби Подхалер is not metabolised, an effect of hepatic impairment on the exposure to Тоби Подхалер is not expected.
Patients after organ transplantation
Adequate data do not exist for the use of Тоби Подхалер 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.
Тоби Подхалер 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 Тоби Подхалер, 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, Тоби Подхалер.
Maximum tolerated daily dose
The maximum tolerated daily dose of Тоби Подхалер has not been established.
Only Тоби Подхалер capsules are to be used in the Podhaler device. No other inhaler may be used.
Тоби Подхалер capsules must always be stored in the blister (capsule card), and only removed immediately before use. Each Podhaler device and its case are used for seven days and then discarded and replaced. Store the Podhaler device in its tightly closed case when not in use.
Basic instructions for use are given below, more detailed instructions are available from the patient leaflet.
1. Wash and fully dry hands.
2. Just before use, remove the Podhaler device from its case. Briefly inspect the inhaler to make sure it is not damaged or dirty.
3. Holding the body of the inhaler, unscrew and remove the mouthpiece from the inhaler body. Set the mouthpiece aside on a clean, dry surface.
4. Separate the morning and evening doses from the capsule card.
5. Peel back the foil from the capsule card to reveal one Тоби Подхалер capsule and remove it from the card.
6. Immediately insert the capsule into the inhaler chamber. Replace the mouthpiece and screw it on firmly until it stops. Do not overtighten.
7. To puncture capsule, hold the inhaler with the mouthpiece down, press the button firmly with your thumb as far as it will go, then release the button.
8. Fully exhale away from the inhaler.
9. Place mouth over the mouthpiece creating a tight seal. Inhale the powder deeply with a single continuous inhalation.
10. Remove inhaler from mouth, and hold breath for approximately 5 seconds, then exhale normally away from the inhaler.
11. After a few normal breaths away from the inhaler, perform a second inhalation from the same capsule.
12. Unscrew mouthpiece and remove the capsule from the chamber.
13. Inspect the used capsule. It should appear punctured and empty.
- If the capsule is punctured but still contains some powder, place it back into the inhaler and take another two inhalations from the capsule. Reinspect capsule.
- If the capsule appears to be unpunctured, place it back into the inhaler, press the button firmly as far as it goes and take another two inhalations from the capsule. After this if the capsule is still full and appears to be unpunctured, replace the inhaler with the reserve inhaler and try again.
14. Discard the empty capsule.
15. Repeat, starting at step 5, for the remaining three capsules of the dose.
16. Replace the mouthpiece and screw it on firmly until it stops. When the full dose (4 capsules) has been inhaled, wipe mouthpiece with a clean dry cloth.
17. Place inhaler back in storage case and close tightly. The inhaler should never be washed with water.
Any unused product or waste material should be disposed of in accordance with local requirements.
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.
