Rocotob

Rocotob (tobramycin ophthalmic ointment) 0.3 % is a topical antibiotic indicated in the treatment of external infections of the eye and its adnexa caused by susceptible bacteria. Appropriate monitoring of bacterial response to topical antibiotic therapy should accompany the use of Rocotob (tobramycin ophthalmic ointment) 0.3%. Clinical studies have shown tobramycin to be safe and effective for use in children.

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

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.

Rocotob 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.

Management of chronic pulmonary infection due to Pseudomonas aeruginosa in patients with cystic fibrosis aged 6 years and older.

In mild to moderate disease, apply a half-inch ribbon into the affected eye(s) two or three times per day. In severe infections, instill a half-inch ribbon into the affected eye(s) every three to four hours until improvement, following which treatment should be reduced prior to discontinuation.

How to Apply Rocotob (tobramycin ophthalmic ointment) 0.3%:

1. Tilt your head back.
2. Place a finger on your cheek just under your eye and gently pull down until a ‘‘V'' pocket is formed between your eyeball and your lower lid.
3. Place a small amount (about 1/2 inch) of Rocotob (tobramycin ophthalmic ointment) 0.3 % in the ‘‘V'' pocket. Do not let the tip of the tube touch your eye.
4. Look downward before closing your eye.

Posology

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

Missed doses

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

Duration of treatment

Treatment with Rocotob Podhaler should be continued on a cyclical basis for as long as the physician considers the patient is gaining clinical benefit from the treatment with Rocotob Podhaler.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 Rocotob Podhaler. Caution should be exercised when prescribing Rocotob Podhaler 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 Rocotob Podhaler 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 Rocotob Podhaler in children aged under 6 years have not been established. No data are available.

Method of administration

Inhalation use.

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

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

Where patients are receiving several different inhaled medicinal products and chest physiotherapy, it is recommended that Rocotob Podhaler 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 Rocotob 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. Rocotob 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 Rocotob 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 Rocotob is not metabolised, an effect of hepatic impairment on the exposure to Rocotob is not expected.

Patients after organ transplantation

Adequate data do not exist for the use of Rocotob 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.

Rocotob 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 Rocotob, 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, Rocotob.

Maximum tolerated daily dose

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

Posology

The dose of Rocotob 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. Rocotob 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 Rocotob should be continued on a cyclical basis for as long as the physician considers the patient is gaining clinical benefit from the treatment with Rocotob.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 Rocotob. Caution should be exercised when prescribing Rocotob 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 Rocotob 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 Rocotob 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 Rocotob 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.

Rocotob capsules must not be swallowed. Each Rocotob 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 Rocotob is taken last.

Rocotob is intended for inhalation only and not for parenteral use.

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

Therapy should be initiated by a physician experienced in the management of cystic fibrosis.

The recommended dose for adults and children above 6 years is one single-dose container (300mg) twice daily (morning and evening) for 28 days. The dose interval should be as close as possible to 12 hours. After 28 days of therapy with Rocotob, patients should stop treatment for the next 28 days. Alternate cycles of 28-days of active therapy followed by 28 days without treatment should be maintained (a cycle of 28 days with therapy and 28 days without treatment).

Children under 6 years old

The efficacy and safety of Rocotob have not been demonstrated in patients less than 6 years of age.

Elderly patients

Tobramycin should be used with caution in elderly patients who may have reduced renal function.

Patients with renal impairment

Tobramycin should be used with caution in patients with known or suspected renal dysfunction. Rocotob should be discontinued in the case of nephrotoxicity until serum concentration of tobramycin fall below 2 µg/mL.

Patients with hepatic insufficiency

No changes in Rocotob dose are required in hepatic insufficiency.

Dosage is not adjusted for body weight. All patients should be administered one single-dose container of Rocotob (300 mg of tobramycin) twice daily.

Treatment with tobramycin should be continued on a cyclical basis for as long as the physician considers the patient is gaining clinical benefit from the inclusion of Rocotob in their treatment regimen. If clinical deterioration of pulmonary status is evident, additional anti-pseudomonal therapy should be considered.

Method of Administration:

The single-dose container should be opened just before use. Any unused solution that is not immediately used should be discarded and not stored for re-use.

Administration of Rocotob should be carried out following general hygienic standards. The apparatus used should be clean and working correctly; the nebuliser, that should be for personal use only, should be kept clean and regularly disinfected.

For cleaning and disinfection of the nebuliser, refer to the instructions provided with the nebuliser.

Maximum tolerated daily dose

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

Instructions for opening the container:

1) Bend the single-dose container in both directions

2) Detach the single-dose container from the strip, firstly above then in the middle

3) Open the single-dose container by rotating the flap as indicated by the arrow

4) Exerting a moderate pressure on the single-dose container's walls, let the medicinal product flow into the glass tube of the nebuliser.

The contents of one single-dose container (300mg) emptied into the nebuliser, should be administered by inhalation over approximately a 15-minute period using a PARI LC PLUS reusable nebuliser equipped with PARI TURBO BOY compressor (drug delivery rate 6.2 mg/min, total drug delivery 92.8 mg, mass median aerodynamic diameter: D₁₀ 0.65 µm, D₅₀ 3.15µm, D₉₀ 8.99µm) or PARI LC SPRINT equipped with compressor PARI BOY Sx (drug delivery rate 6.7 mg/min, total drug delivery 99.8 mg, mass median aerodynamic diameter: D₁₀ 0.70 µm, D₅₀ 3.36µm, D₉₀ 9.41µm)

Rocotob is inhaled while the patient is sitting or standing upright and breathing normally through the mouthpiece of the nebuliser. Nose clips may help the patient with breathing through the mouth. The patient should continue their standard regimen of chest physiotherapy. The use of appropriate bronchodilators should continue as thought clinically necessary. In patients receiving several different respiratory therapies, it is recommended that they are taken in the following order: bronchodilator, respiratory physiotherapy, other inhaled medicinal products, and finally Rocotob.

Rocotob should not be mixed with other inhalation medicinal products.

WARNINGS

NOT FOR INJECTION INTO THE EYE. Sensitivity to topically applied aminoglycosides may occur in some patients. If a sensitivity reaction to Rocotob (tobramycin ophthalmic ointment) 0.3 % occurs, discontinue use.

PRECAUTIONS

General

As with other antibiotic preparations, prolonged use may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, appropriate therapy should be initiated. Ophthalmic ointments may retard corneal wound healing. Cross-sensitivity to other aminoglycoside antibiotics may occur; if hypersensitivity develops with this product, discontinue use and institute appropriate therapy. Patients should be advised not to wear contact lenses if they have signs and symptoms of ocular infections.

Pregnancy Category B

Reproduction studies in three types of animals at doses up to thirty-three times the normal human systemic dose have revealed no evidence of impaired fertility or harm to the fetus due to tobramycin. There are, however, no adequate and well-controlled studies in pregnant women. Because animal studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Nursing Mothers

Because of the potential for adverse reactions in nursing infants from Rocotob® (tobramycin ophthalmic ointment) 0.3 %, a decision should be made whether to discontinue nursing the infant or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in pediatric patients below the age of 2 months has not been established.

Geriatric Use

No overall clinical differences in safety or effectiveness have been observed between the elderly and other adult patients.

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 Rocotob Podhaler clinical studies. Caution should be exercised when prescribing Rocotob Podhaler to patients with known or suspected auditory or vestibular dysfunction.

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

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

See also “Monitoring of serum tobramycin concentrations” below.

Nephrotoxicity

Nephrotoxicity has been reported with the use of parenteral aminoglycosides. Nephrotoxicity was not observed during Rocotob Podhaler clinical studies. Caution should be exercised when prescribing Rocotob Podhaler to patients with known or suspected renal dysfunction. Baseline renal function should be assessed. Urea and creatinine levels should be reassessed after every 6 complete cycles of Rocotob Podhaler therapy.

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 Rocotob Podhaler, tobramycin therapy should be discontinued until serum concentration falls below 2 µg/ml.

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

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

Bronchospasm

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

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

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

Cough

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

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

Haemoptysis

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

Other precautions

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

See also “Monitoring of serum tobramycin concentrations” above.

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

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

There is a theoretical risk that patients being treated with Rocotob Podhaler 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 Rocotob Podhaler versus tobramycin nebuliser solution, which included a majority of tobramycin-experienced adult patients with chronic pulmonary P. aeruginosa infection, the suppression of sputum P. aeruginosa density was similar across age groups in both arms; however the increase from baseline FEV₁ was larger in younger age groups (6 - <20) than in the adult subgroup (20 years and older) in both arms.

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 Rocotob Podhaler.

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

Rocotob 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 Rocotob concentrations

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

Serum concentrations of Rocotob 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 Rocotob 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 Rocotob. Furthermore, the contamination cannot be avoided by hand washing before testing.

Bronchospasm

Bronchospasm can occur with nebulised Rocotob, as is the case with other inhaled medicinal products. The first dose of Rocotob 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 Rocotob should be discontinued. Bronchospasm should be treated as medically appropriate.

Neuromuscular disorders

Rocotob 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 Rocotob.

The product should be used with caution in patients with known or suspected renal dysfunction and serum Rocotob 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 Rocotob therapy (180 days of nebulised aminoglycoside therapy). If there is any evidence of nephrotoxicity, all Rocotob therapy should be discontinued until trough serum Rocotob concentrations fall below 2 µg/mL. Rocotob 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 Rocotob 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 Rocotob 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 Rocotob 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 Rocotob 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 Rocotob 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 Rocotob show an increase in aminoglycoside Minimum Inhibitory Concentrations of P. aeruginosa isolates tested. There is a theoretical risk that patients being treated with nebulised Rocotob may develop P. aeruginosa isolates resistant to intravenous Rocotob.

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 Rocotob clinical studies. Caution should be exercised when prescribing Rocotob 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 Rocotob therapy.

If a patient reports tinnitus or hearing loss during Rocotob 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 Rocotob clinical studies. Caution should be exercised when prescribing Rocotob 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 Rocotob 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 Rocotob, 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 Rocotob in clinical studies. Bronchospasm should be treated as medically appropriate.

The first dose of Rocotob 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 Rocotob.

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

Cough

Cough was reported with use of Rocotob in clinical studies. Based on clinical trial data the inhalation powder Rocotob 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 Rocotob compared with older subjects.

If there is evidence of continued therapy-induced cough with Rocotob, 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 Rocotob in these patients. This should be taken into account before prescribing Rocotob, considering the inhalation powder Rocotob was associated with a higher rate of cough (see above). The use of Rocotob 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 Rocotob therapy.

See also “Monitoring of serum tobramycin concentrations” above.

Caution should be exercised when prescribing Rocotob 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 Rocotob 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 Rocotob 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 Rocotob 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 Rocotob.

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

Tobramycin should be used with caution in patients with known or suspected renal, auditory, vestibular or neuromuscular dysfunction, or with severe, active haemoptysis.

Renal and eighth cranial nerve function should be closely monitored in patients with known or suspected renal impairment and also in those whose renal function is initially normal but who develop signs of renal dysfunction during therapy. Evidence of impairment in renal, vestibular and/or auditory function requires discontinuation of the drug or dosage adjustment.

The serum concentration of tobramycin should only be monitored through venipuncture and not finger prick blood sampling which is a non validated dosing method. It has been observed that contamination of the skin of the fingers from the preparation and nebulisation of tobramycin may lead to falsely increased serum levels of the drug. This contamination cannot be completely avoided by hand washing before testing.

Bronchospasm

Bronchospasm can occur following inhalation of medicinal products and has been reported with nebulised tobramycin. The first dose of Rocotob should be given under medical supervision, using a pre-nebulisation bronchodilator if this is already part of the current treatment regimen for the patient. FEV₁ (forced expiratory volume) should be measured before and after nebulisation. If there is evidence of therapy-induced bronchospasm in a patient not receiving a bronchodilator, the test should be repeated on a separate occasion, using a bronchodilator. Onset of bronchospasm in the presence of bronchodilator therapy may indicate an allergic reaction. Should an allergic reaction be suspected, Rocotob should be discontinued. Bronchospasm should be treated as clinically appropriate.

Neuromuscular disorders

Tobramycin should be used with great caution in patients with neuromuscular disorders, such as parkinsonism or other conditions characterised by myasthenia, including myasthenia gravis, as aminoglycosides may worsen muscular weakness due to a potential curare-like effect on the neuromuscular function.

Nephrotoxicity

Although nephrotoxicity has been associated with parenteral aminoglycoside therapy, there was no evidence of nephrotoxicity during clinical trials with tobramycin. The product should be used with caution in patients with known or suspected renal dysfunction and tobramycin serum concentrations should be monitored, e.g. serum level assays after two or three doses should be performed, so that the dosage could be adjusted if necessary, and also at three to four day intervals during therapy. In the event of changing renal function, more frequent serum levels should be obtained and the dosage or dosage intervals adjusted. 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 recommends that baseline renal function should be assessed. Furthermore, the renal function should be periodically reassessed, by regularly monitoring urea and creatinine levels at least every 6 full cycles of therapy with tobramycin (180-day treatment with nebulised tobramycin). If there is evidence of nephrotoxicity, therapy with tobramycin should be discontinued until the drug minimum serum concentrations fall below 2 μg/ml. Tobramycin therapy may then be resumed following medical advice. Patients receiving concomitant parenteral aminoglycoside therapy should be strictly monitored, due to the risk of cumulative toxicity.

Monitoring of renal function is particular important in elderly patients who may have reduced renal function that may not be evident in the results of routine screening tests, such as blood urea or serum creatinine. A creatinine clearance determination may be more useful.

Urine should be examined for increased excretion of protein, cells and casts. Serum creatinine or creatinine clearance (preferred over blood urea) should be measured periodically.

Ototoxicity

Ototoxicity, manifested as both auditory and vestibular toxicity has been reported with the parenteral aminoglycosides. Vestibular toxicity may be manifested by vertigo, ataxia or dizziness.

During controlled clinical studies with tobramycin, modest hypoacusia and vertigo were observed, while with other nebulised tobramycin containing medicines auditory toxicity, as measured by complaints of hearing loss or by audiometric evaluations did not occur during controlled clinical studies.

In open label studies and post-marketing experience, some patients with a history of prolonged previous or concomitant use of intravenous aminoglycosides have experienced hearing loss.

The physician should consider the possibility that aminoglycosides may cause vestibular and cochlear toxicity and should assess auditory function throughout the treatment period with Rocotob. In patients with a predisposing risk due to previous prolonged systemic therapy with aminoglycosides, it may be necessary to consider audiological assessment before starting therapy with tobramycin. The occurrence of tinnitus warrants caution, since it represents an ototoxic symptom. If the patient reports about tinnitus or hearing loss during the therapy with aminoglycosides, the physician should consider whether audiologic tests are necessary. When feasible, it is recommended that serial audiograms are performed in patients on continuous therapy, which are at particular high risk of ototoxicity. Patients receiving concomitant parenteral therapy with aminoglycosides should be monitored as clinically appropriate, taking into account the risk of cumulative toxicity.

Haemoptysis

Inhalation of nebulised solutions may induce a cough reflex. The use of nebulised Rocotob in patients with active, severe haemoptysis should be undertaken only if the benefits of treatment are considered to outweigh the risks of inducing further haemorrhage.

Microbial Resistance

In clinical studies, some patients treated with nebulised tobramycin showed an increase in aminoglycoside Minimum Inhibitory Concentrations for P. aeruginosa isolates tested.).“Pregnancy and lactation”.

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

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

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

No studies on the effect on the ability to drive and use machines have been performed. On the basis of reported adverse drug reactions, tobramycin is presumed to be unlikely to produce an effect on ability to drive and use machinery.

Nevertheless, since dizziness and/or vertigo may occur, patients who are going to drive or use machinery should be alerted.

The most frequent adverse reactions to Rocotob (tobramycin ophthalmic ointment) 0.3% are hypersensitivity and localized ocular toxicity, including lid itching and swelling, and conjunctival erythema. These reactions occur in less than three of 100 patients treated with Rocotob (tobramycin ophthalmic ointment) 0.3%. Similar reactions may occur with the topical use of other aminoglycoside antibiotics. Other adverse reactions have not been reported from Rocotob (tobramycin ophthalmic ointment) 0.3% therapy; however, if topical ocular tobramycin is administered concomitantly with systemic aminoglycoside antibiotics, care should be taken to monitor the total serum concentration. In clinical trials, Rocotob (tobramycin ophthalmic ointment) 0.3% produced significantly fewer adverse reactions (3.7%) than did GARAMYCIN® Ophthalmic Ointment (10.6%).

Summary of the safety profile

The most commonly reported adverse reactions in the main safety, active-controlled clinical study with Rocotob 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 Rocotob Podhaler, the adverse reactions for which reported frequency was higher with Rocotob Podhaler than with placebo were pharyngolaryngeal pain, dysgeusia and dysphonia.

The vast majority of adverse reactions reported with Rocotob 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

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 Rocotob 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 Rocotob 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 Rocotob 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 Rocotob than in the control group; (13% Rocotob vs 7% control) and (3% Rocotob vs 0% control), respectively. The episodes of tinnitus were transient and resolved without discontinuation of Rocotob 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 Rocotob.

Additional undesirable effects, some of which are common sequelae of the underlying disease, but where a causal relationship to Rocotob 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..

Summary of the safety profile

The most commonly reported adverse reactions in the main safety, active-controlled clinical study with Rocotob 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 Rocotob, the adverse reactions for which reported frequency was higher with Rocotob than with placebo were pharyngolaryngeal pain, dysgeusia and dysphonia.

The vast majority of adverse reactions reported with Rocotob 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

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 Rocotob 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 Rocotob 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 (4) and uncontrolled clinical trials (1) with Rocotob (565 patients treated), the most common reactions were those concerning the respiratory tract (cough and dysphonia).

The adverse reactions reported in the clinical trials (see below) are classified as: common (>1/100 and <1/10); uncommon (>1/1,000 to <1/100); rare (>1/10,000 and <1/1,000); very rare (<1/10,000).

In controlled clinical trials with other nebulised tobramycin containing medicines, dysphonia and tinnitus were the only undesirable effects reported in significantly more patients treated with tobramycin; (13% tobramycin vs. 7% control) and (3% tobramycin vs. 0% control) respectively. These episodes of tinnitus were transient and resolved without discontinuation of tobramycin therapy, and were not associated with permanent loss of hearing on audiogram testing. The risk of tinnitus did not increase with repeated cycles of exposure to tobramycin.

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

In addition, cumulative post-marketing data with products containing nebulised tobramycin reported the following adverse reactions (same frequency classification reported above):

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).

“Contraindications” and 4.4 “Special warnings and precautions for use”).

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.

Clinically apparent signs and symptoms of an overdose of Rocotob (tobramycin ophthalmic ointment) 0.3% (punctate keratitis, erythema, increased lacrimation, edema and lid itching) may be similar to adverse reaction effects seen in some patients.

Adverse reactions specifically associated with overdose of Rocotob Podhaler have not been identified. The maximum tolerated daily dose of Rocotob Podhaler has not been established. Tobramycin serum concentrations may be helpful in monitoring overdosage. In case of signs of acute toxicity, immediate withdrawal of Rocotob Podhaler and testing of renal function are recommended. In the event of accidental oral ingestion of Rocotob 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.

Inhalation of Rocotob 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 Rocotob is poorly absorbed from the gastrointestinal tract.

In the case of inadvertent intravenous administration of Tymbrineb Nebuliser Solution, signs and symptoms of parenteral Rocotob 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 Rocotob and baseline renal function testing. Serum Rocotob concentrations may be helpful in monitoring overdose. In the case of overdosage, the possibility of drug interactions with alterations in the elimination of Rocotob or other medicinal products should be considered.

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

Symptoms

Administration by inhalation results in low systemic bioavailability of tobramycin. Symptoms of aerosol overdose may include severe hoarseness.

In the event of accidental ingestion of Rocotob, toxicity is unlikely as tobramycin is poorly absorbed from an intact gastrointestinal tract.

In the event of inadvertent intravenous administration of Rocotob, signs and symptoms of parenteral tobramycin overdose may occur, such as dizziness, tinnitus, vertigo, hearing loss, respiratory distress and/or neuromuscular blockade and renal impairment.

Treatment

Acute toxicity should be treated with immediate withdrawal of Rocotob, and baseline tests of renal function should be carried out. Tobramycin serum concentrations may be helpful in monitoring overdose. In case of any overdose, the possibility of drug interactions with alterations in the elimination of Rocotob or other medicinal products should be considered.

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 (Rocotob) 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 Rocotob Podhaler therapy as follows:

Clinical experience

The Rocotob 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, Rocotob 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 Rocotob 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.

Rocotob 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 Rocotob Podhaler.

When patients in the placebo treatment group were switched from placebo to Rocotob Podhaler at the start of the second treatment cycle, they experienced a similar improvement from baseline in percent predicted FEV₁. Treatment with Rocotob 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 Rocotob Podhaler (112 mg) or tobramycin 300 mg/5 ml nebuliser solution (Rocotob), administered twice daily for three cycles. A majority of the patients were tobramycin-experienced adults with chronic pulmonary P. aeruginosa infection.

Treatment with both Rocotob Podhaler and tobramycin 300 mg/5 ml nebuliser solution (Rocotob) 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 Rocotob Podhaler treatment group and was statistically non-inferior to Rocotob 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 Rocotob Podhaler and Rocotob 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 Rocotob Podhaler and 22.0% with Rocotob 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 Rocotob 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 Rocotob Podhaler and 0.9% with Rocotob nebuliser solution).

Furthermore, an improvement of 6% in percent predicted FEV₁ was obtained in about 30% versus 36% of the adult patients in the Rocotob Podhaler and Rocotob nebuliser solution group respectively.

Treatment with Rocotob 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 Rocotob 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 Rocotob Podhaler compared with tobramycin nebuliser solution in each cycle.

Paediatric population

Pharmacotherapeutic group: Aminoglycoside Antibacterials,

ATC code: JO1GB01

Mechanism of action

Rocotob 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 Rocotob can occur via several mechanisms including: alterations of the ribosomal subunit within the bacterial cell, interference with the transport of Rocotob into the cell and inactivation of Rocotob 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 Rocotob use and might not be applicable to nebulised Rocotob. In accordance with CPMP/EWP/558/95 rev.1, the following Minimum Inhibitory Concentration (MIC) breakpoints are defined for Rocotob 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 Rocotob 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 Rocotob 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 Rocotob achieved sputum concentrations 10 fold the highest P. aeruginosa MIC cultured from the patient and 95% of patients receiving inhaled Rocotob 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 Rocotob. 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 Rocotob MICs <128 µg/ml at baseline showed improved lung function after treatment with inhaled Rocotob. 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 Rocotob had improved lung function.

Over the entire 96 week duration of the extension studies, the Rocotob 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 Rocotob showed a small but clear increase in Rocotob, 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 Rocotob were at greater risk for acquiring B. cepacia, S. matlophilia or A. xylosoxidans, than would be expected in patients not treated with Rocotob. Aspergillus species were more frequently recovered from the sputum of patients receiving Rocotob; 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 Rocotob. 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 Rocotob 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 Rocotob therapy on an outpatient basis using a hand-held PARI LC PLUS™ Reusable Nebuliser with a DeVilbiss® Pulmo-Aide® compressor.

In each study, Rocotob-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 Rocotob 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 Rocotob for 48, 72 and 96 weeks respectively. The rate of lung function decline was significantly lower following initiation of Rocotob 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 Rocotob treatment.

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 Rocotob therapy as follows:

Clinical experience

The Rocotob 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, Rocotob 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 Rocotob in the subsequent two cycles. Patients in this study had no exposure to inhaled tobramycin for at least 4 months prior to study start.

Rocotob 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 Rocotob.

When patients in the placebo treatment group were switched from placebo to Rocotob at the start of the second treatment cycle, they experienced a similar improvement from baseline in percent predicted FEV₁. Treatment with Rocotob 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 Rocotob (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 Rocotob 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 Rocotob 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 Rocotob 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 Rocotob 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 Rocotob 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 Rocotob 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 Rocotob and TOBI nebuliser solution group respectively.

Treatment with Rocotob 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 Rocotob 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 Rocotob 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 Rocotob 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: J01GB01.

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. Cystic fibrosis (CF) sputum exhibits an inhibitory action on the local biological activity of nebulised aminoglycosides. This necessitates sputum concentrations of aerosolised tobramycin to be some ten and twenty-five fold above the Minimum Inhibitory Concentration (MIC) for, respectively, P. aeruginosa growth suppression and bactericidal activity. In controlled clinical trials, 90% of patients receiving tobramycin achieved sputum concentrations 10 fold the highest P. aeruginosa MIC cultured from the patient, and 84% of patients receiving tobramycin 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.

Susceptibility

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 tobramycin.

In clinical studies with inhaled tobramycin, most patients (88%) with P. aeruginosa isolates with tobramycin MICs <128 µg/mL at baseline showed improved lung function following treatment with tobramycin. Patients with a P. aeruginosa isolate with a MIC > 128 µg/mL at baseline are less likely to show a clinical response.

Based upon in vitro data and/or clinical trial experience, the organisms associated with pulmonary infections in CF may be expected to respond to tobramycin therapy as follows:

Treatment with tobramycin regimen in clinical studies showed a small but clear increase in tobramycin, amikacin and gentamicin Minimum Inhibitory Concentrations for P. aeruginosa isolates tested. Each additional 6 months of treatment resulted in incremental increases similar in magnitude to that observed in the 6 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 is characterised by a reversion to susceptibility when the antibiotic is removed.

Other Information

In controlled clinical studies, treatment with Rocotob carried out according to alternate cycles as described above, led to an improvement in lung function, with results maintained above baseline throughout therapy and 28 day periods off therapy.

In clinical trials with tobramycin there are no data in patients aged less than 6 years.

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

Absorption

The systemic exposure to tobramycin after inhalation of Rocotob 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 Rocotob Podhaler in cystic fibrosis patients, the maximum serum concentration (C_max) of tobramycin was 1.02 ± 0.53 μg/ml (mean ± SD) and the median time to reach the peak concentration (T_max) was one hour. In comparison, after inhalation of a single dose of tobramycin 300 mg/5 ml nebuliser solution (Rocotob), C_max was 1.04 ± 0.58 µg/ml and median T_max was one hour. The extent of systemic exposure (AUC) was also similar for the 112 mg Rocotob Podhaler dose and the 300 mg tobramycin nebuliser solution dose. At the end of a 4-week dosing cycle of Rocotob 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 Rocotob Podhaler in cystic fibrosis patients, sputum C_max of tobramycin was 1047 ± 1080 µg/g (mean ± SD). In comparison, after inhalation of a single 300 mg dose of tobramycin nebuliser solution (Rocotob), sputum C_max 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 Rocotob 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 (C_max) and trough (C_trough) 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 Rocotob 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 (Rocotob).

A population pharmacokinetic analysis for Rocotob 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

Absorption

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

Sputum concentrations: Ten minutes after the first inhalation of Rocotob 300 mg, the average sputum concentration of Rocotob was 1,237 µg/g (range: 35 to 7,414 µg/g). There is no accumulation of Rocotob in the sputum; after 20 weeks of therapy with the Rocotob regimen, the average sputum concentration of Rocotob 10 minutes after inhalation was 1,154 µg/g (range: 39 to 8,085 µg/g). High variability of sputum Rocotob 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 Rocotob, 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 Rocotob 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 Rocotob dose of 1.5 to 2 mg/kg typically range from 4 to 12 µg/ml.

Distribution

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

Biotransformation

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

Elimination

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

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

Renal function is expected to affect the exposure to Rocotob, 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 Rocotob is probably eliminated in expectorated sputum.

Absorption

The systemic exposure to tobramycin after inhalation of Rocotob 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 Rocotob in cystic fibrosis patients, the maximum serum concentration (C_max) of tobramycin was 1.02 ± 0.53 μg/ml (mean ± SD) and the median time to reach the peak concentration (T_max) was one hour. In comparison, after inhalation of a single dose of tobramycin 300 mg/5 ml nebuliser solution (TOBI), C_max was 1.04 ± 0.58 µg/ml and median T_max was one hour. The extent of systemic exposure (AUC) was also similar for the 112 mg Rocotob dose and the 300 mg tobramycin nebuliser solution dose. At the end of a 4-week dosing cycle of Rocotob (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 Rocotob in cystic fibrosis patients, sputum C_max 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 C_max 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 Rocotob 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 (C_max) and trough (C_trough) 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 Rocotob 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 Rocotob 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 and distribution

Following oral administration only 0.3-0.5% of the drug appears in urine to prove systemic absorption. After administration via nebuliser in 6 cystic fibrosis patients, mean absolute bioavailability was about 9.1% of the dose. Systemic absorption of tobramycin is very low when administered by aerosol inhalation, with a limited uptake of the inhaled drug into the systemic circulation, it is estimated that approximately 10% of the mass of drug initially nebulised is deposited in the lungs and the remaining 90% either remains in the nebuliser, is impacted on the oro-pharynx and swallowed, or is exhaled into the atmosphere.

Sputum concentrations: Ten minutes after inhalation of the first 300 mg dose of Rocotob, the average sputum concentration of tobramycin was 695.6 μg/g (range: 36 to 2,638 μg/g). Tobramycin does not accumulate in sputum; after 20 weeks of therapy with the Rocotob regimen, the average sputum concentration of tobramycin 10 minutes after inhalation was 716.9 μg/g (range: 40 to 2,530 μg/g). High variability of sputum tobramycin concentrations was observed. Two hours after inhalation, sputum concentrations declined to approximately 14% of tobramycin levels measured at 10 minutes after inhalation.

Serum concentrations: The median serum concentration of tobramycin 1 hour after inhalation of a single 300 mg dose of Rocotob by CF patients was 0.68 μg/mL (range: 0.06μg/mL - 1.89μg/mL). After 20 weeks of therapy on the tobramycin regimen, the median serum tobramycin concentration 1 hour after dosing was 1.05 μg/mL (range: BLQ- 3.41μg/mL).

Elimination

The elimination of tobramycin administered by the inhalation route has not been studied.

Following intravenous administration, systemically absorbed tobramycin is eliminated principally by glomerular filtration. The elimination half-life of tobramycin from serum is approximately 2 hours. Less than 10% of tobramycin is bound to plasma proteins.

Unabsorbed tobramycin following tobramycin administration is probably eliminated primarily in expectorated sputum.

Only Rocotob Podhaler capsules are to be used in the Podhaler device. No other inhaler may be used.

Rocotob 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 Rocotob 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.

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.

Only Rocotob capsules are to be used in the Podhaler device. No other inhaler may be used.

Rocotob 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 Rocotob 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.

For single use only.

Use immediately after first opening the single-dose container. Discard the used single-dose container immediately.

Any waste material should be discarded after use.