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.
3 years
Discard the Podhaler device and its case 1 week after first use.
Not applicable
Capsule content
1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)
Calcium chloride
Sulfuric acid (for pH adjustment)
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 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 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: mhra.gsi.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
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.
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 TOBI Podhaler therapy as follows:
|
Susceptible |
Pseudomonas aeruginosa Haemophilus influenzae Staphylococcus aureus |
|
Insusceptible |
Burkholderia cepacia Stenotrophomonas maltophilia Alcaligenes xylosoxidans |
Clinical experience
The TOBI Podhaler 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, TOBI Podhaler 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 TOBI Podhaler in the subsequent two cycles. Patients in this study had no exposure to inhaled tobramycin for at least 4 months prior to study start.
TOBI Podhaler 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 TOBI Podhaler.
When patients in the placebo treatment group were switched from placebo to TOBI Podhaler at the start of the second treatment cycle, they experienced a similar improvement from baseline in percent predicted FEV1. Treatment with TOBI Podhaler 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 TOBI Podhaler (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 TOBI Podhaler 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 TOBI Podhaler 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 TOBI Podhaler 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 TOBI Podhaler 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 TOBI Podhaler 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 TOBI Podhaler 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 TOBI Podhaler and TOBI nebuliser solution group respectively.
Treatment with TOBI Podhaler 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 TOBI Podhaler 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 TOBI Podhaler 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 TOBI Podhaler 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).
Absorption
The systemic exposure to tobramycin after inhalation of TOBI Podhaler 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 TOBI Podhaler 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 TOBI Podhaler dose and the 300 mg tobramycin nebuliser solution dose. At the end of a 4-week dosing cycle of TOBI Podhaler (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 TOBI Podhaler 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 TOBI Podhaler 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 TOBI Podhaler 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 TOBI Podhaler 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
23 April 2018
Novartis Europharm Limited
Vista Building
Elm Park, Merrion Road
Dublin 4
Ireland
TOBI Podhaler capsules must always be stored in the blister to protect from moisture and only removed immediately before use.
The hard capsules are supplied in PVC/PA/Alu/PVC- PET/Alu blisters.
The Podhaler inhalation device and its storage case are made from plastic materials (polypropylene).
TOBI Podhaler is supplied in monthly packs containing 4 weekly cartons and a reserve Podhaler device in its storage case. Each weekly carton contains 56 x 28 mg capsules (7 blisters with 8 capsules per blister), and a Podhaler device in its storage case.
Pack sizes:
56 capsules and 1 inhaler
224 (4 x 56) capsules and 5 inhalers (monthly multipack)
448 (8 x 56) capsules and 10 inhalers (2 x monthly multipack wrapped in foil)
Not all pack sizes may be marketed.
EU/1/10/652/001-003
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. 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.
TOBI Podhaler has no or negligible influence on the ability to drive and use machines.
Only TOBI Podhaler capsules are to be used in the Podhaler device. No other inhaler may be used.
TOBI Podhaler 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 TOBI Podhaler 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.
Date of first authorisation: 20 July 2011
Date of latest renewal: 18 February 2016
