Bramitob 300mg/4ml Nebuliser Solution

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
Tobramycin
Available from:
Chiesi Limited
ATC code:
J01GB; J01GB01
INN (International Name):
Tobramycin
Dosage:
300/4 milligram(s)/millilitre
Pharmaceutical form:
Nebuliser solution
Prescription type:
Product subject to prescription which may not be renewed (A)
Therapeutic area:
Other aminoglycosides; tobramycin
Authorization status:
Marketed
Authorization number:
PA0743/017/001
Authorization date:
2007-06-01

CHIESI ITEM

PACKAGE LEAFLET: INFORMATION FOR THE USER

Bramitob 300mg/4ml Nebuliser Solution

Tobramycin

Read all of this leaflet carefully before you start using this medicine because it con-

tains important information for you.

- Keep this leaflet. You may need to read it again.

- If you have any further questions, ask your doctor or pharmacist.

- This medicine has been prescribed for you only. Do not pass it on to others. It may

harm them, even if their signs of illness are the same as yours.

- If you get any side effects, talk to your doctor or pharmacist. This includes any possible

side effects not listed in this leaflet. See section 4.

What is in this leaflet:

1. What Bramitob is and what it is used for

2. What you need to know before you use Bramitob

3. How to use Bramitob

4. Possible side effects

5. How to store Bramitob

6. Contents of the pack and other information

1. What Bramitob is and what it is used for

Bramitob contains tobramycin which is an antibiotic belonging to a family called the

aminoglycosides. It fights infections caused by Pseudomonas aeruginosa.

Bramitob is used for treating chronic chest infections in patients with cystic fibrosis caused by

Pseudomonas bacteria. It kills the bacteria and helps to improve your breathing. Pseudomonas

is a very common bacterium that infects nearly all patients with cystic fibrosis at some time

during their lives. Some people do not get this infection until later on in their lives while others

get it very young. If infection is not properly controlled it will continue to damage the lungs

causing further problems. As Bramitob is breathed-in the antibiotic, tobramycin, can get straight

into your lungs to work against the bacteria causing the infection.

Bramitob is indicated only for patients aged 6 years and older.

To achieve the best results please make every effort to use your medicine as instructed.

2. What you need to know before you use Bramitob

Do not use Bramitob:

If you are allergic (hypersensitive) to tobramycin, any of the other ingredients of

this medicine (listed in section 6) or any other type of aminoglycoside antibiotic

If you are taking any of the medicines listed in the section below, Taking other medicines

Warnings and precautions

Talk to your doctor or pharmacist before using Bramitob.

The tobramycin in Bramitob is one of a group of medicines that can occasionally cause hearing

loss, dizziness and kidney damage (see also Section 4 on the back of the leaflet, Possible

side effects). It is important that you tell your doctor if any of the following applies to you:

If your chest becomes tight after using your Bramitob. Your doctor will supervise

your first dose of Bramitob and check your lung function before and after dosing. If

you are not already doing so, your doctor may ask you to use a bronchodilator, (e.g.

salbutamol), before using Bramitob.

If you have ever suffered from any neuromuscular disorders such as parkinsonism

or other conditions characterised by muscle weakness, including myasthenia gravis.

If you have ever experienced kidney problems in the past. Before you start to use

Bramitob, your doctor may check that your kidneys are working properly by testing a

blood or urine sample. Your doctor may re-check this regularly during treatment.

If you have ever experienced in the past

- ringing in your ears

- any other problems with your hearing

- dizziness.

Your doctor may test your hearing before starting Bramitob or at any time during your Bramitob

treatment.

If you are currently coughing up blood in your sputum. Inhaling medicines may cause

you to cough and your doctor may ask you to stop using Bramitob until little or no

blood appears in your sputum.

If you are concerned that your Bramitob is not as effective as it should be. Bacteria

can sometimes develop resistance to antibiotic treatment.

Other medicines and Bramitob

Before starting treatment, please tell your doctor or pharmacist if you are taking or have

recently taken or might take any other medicines, including medicines obtained without a

prescription.

Do not use Bramitob if you are taking diuretics (water tablets) containing furosemide

or ethacrynic acid, without discussing this with your doctor.

Do not use Bramitob if you are taking urea or intravenous and oral mannitol (these pro

ducts are used to treat serious conditions in hospitalised patients).

Some other medicines can sometimes harm the kidneys or hearing and this could be

made worse by Bramitob treatment.

You may be receiving injections of tobramycin or other aminoglycosides as well as inhaling

Bramitob. Such injections, which may increase the very low body levels of aminoglycoside

caused by inhaling Bramitob, should be avoided when the following medicines are being taken:

Amphotericin B, cefalotin, ciclosporin, tacrolimus, polymyxins

Platinum compounds (for example, carboplatin and cisplatin)

Anticholinesterases (for example, neostigmine and pyridostigmine), botulinum toxin

If this applies to you, you should speak to your doctor.

Pregnancy and breast-feeding

If you are pregnant or breastfeeding, think you may be pregnant or are planning to have a

baby, ask your doctor or pharmacist for advice before using this medicine.

Driving and using machines

Bramitob has minor influence on the ability to drive and use machines.

In rare cases Bramitob may make you feel dizzy. It is therefore possible that Bramitob could

affect your ability to drive a car or operate machinery.

3. How to use Bramitob

Always use this medicine exactly as your doctor has told you. Check with your doctor or

pharmacist if you are not sure. Instructions for using Bramitob are given after the dosage

section.

Do not mix or dilute your Bramitob with any other medicine in your nebuliser.

If you are taking several different treatments for cystic fibrosis you should take them in the

following order:

- bronchodilator (e.g. salbutamol), then

- chest physiotherapy, then

- other inhaled medicines, then

- Bramitob

Also check the order with your doctor.

Bramitob should be used with a clean, dry PARI LC PLUS or PARI LC SPRINT reusable

nebuliser (for your own personal use only) and a suitable compressor. Ask your doctor or

physiotherapist for advice on which compressor to use.)

The single-dose Bramitob container should be opened just before use. Any unused solution

that is not immediately used should be discarded.

Dosage

The dose (one 4 ml container) is the same for all persons aged 6 years and older.

Use two single-dose containers per day for 28 days. Inhale the contents of one

container in the morning and one in the evening. There should be a 12 hour gap

between the doses.

You then have 28 days without taking your medicine before starting another 28-day

treatment cycle again.

It is important that you keep using the product twice each day during your 28 days on

treatment and that you keep to the 28-day on/28-day off cycle. Keep taking Bramitob

in this way until your doctor tells you to stop.

If you use more Bramitob than you should

If you inhale too much Bramitob you may get a very hoarse voice. Make sure you tell your

doctor as soon as possible.

If you forget to use Bramitob

If there are more than 6 hours before you are due to use your next dose (container),

use Bramitob now.

If there are less than 6 hours before you are due to use your next dose (container),

miss out the forgotten dose (container).

Then continue with your next dose as normal.

Please read back of leaflet

CHIESI FARMACEUTICI S.p.A. - Parma - Italy

NOT TO TAMPER THIS DOCUMENT

Artwork Owner: MS- mail: m.sigurani@chiesi.com

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I certify here by under my personal responsibility that the signed text is in full compliance with the official version approved

by the relevant regulatory Authority and in agreement with all regulations in force in the country, where the product will be

distributed.

Approved & Proceed

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Reason of the change:

Text for SUBMISSION: National Phase Type II Local Approval

Text received on 26/02/2019 From: Ch.Ltd

1

01/03/19

2

CH.Ltd: text correction

01/03/19

3

CH.Ltd: text correction

FRONT

PAG. 1/2

Instructions for use

Bramitob is intended for use in a nebuliser, do not use it in any other way.

Wash your hands thoroughly with soap and water before opening your single-dose

container according to the following instructions.

Bend the single-dose container backwards and forwards (Figure A).

Carefully separate a new container from the strip, firstly from the top, then in the middle

(Figure B), leaving the rest in the foil envelope.

Open the single-dose container by rotating the flap as indicated by the arrow (Figure C).

Gently squeeze the contents of the container into the nebuliser chamber (Figure D).

Turn on the compressor.

Check if there is a steady mist coming from the mouthpiece.

Sit or stand in an upright position so that you can breathe normally.

Place the mouthpiece between your teeth and on top of your tongue. Breathe normally,

but only through your mouth (you may find noseclips helpful). Try not to block the end of

the mouthpiece with your tongue.

10. Continue until all the Bramitob is used up, this should take about 15 minutes.

11. If you are interrupted, or need to cough or rest during your treatment, turn off the

compressor to save your medicine. Turn the compressor on again when you are ready

to restart your treatment.

If you have any further questions on the use of this product, ask your doctor or pharmacist.

Looking after your nebuliser and compressor:

Please follow the manufacturer’s instructions for the care and use of your nebuliser and

compressor.

4. Possible side effects

Like all medicines, Bramitob can cause side effects, although not everybody gets them.

If you are not sure what the side effects below are, ask your doctor to explain them to you.

The most common side effects of Bramitob which may affect more than 1 in 100 people are:

Cough and hoarseness.

Uncommon side effects of Bramitob which may affect more than 1 in 1,000 people are: thrush

in the mouth (candida infection), vertigo, loss of hearing, increased saliva quantities,

inflammation of the tongue, rash, sore throat, hepatic enzymes increased in the blood, noisy

breathing, nausea, mucosal dry, coughing up blood, pain in the throat (oropharyngitis) or chest,

loss of hearing, headache, shortness of breath, weakness, producing more sputum (the sub-

stance you cough up) than normal, gastric pain and fungal infection.

Rare side effects which may affect more than 1 in 10,000 people are: loss of appetite, ringing

in the ears, chest tightness or difficulty breathing, loss of voice, nose bleeds, runny nose,

mouth ulcers, vomiting, taste disturbances, asthma, dizziness, loss of strength, fever, pain,

laryngitis (voice alteration with sore throat and difficulty swallowing).

Very Rare side effects which may affect less than 1 in 10,000 people are: swelling of lymph

glands, drowsiness, ear problems, ear pain, hyperventilation, sinusitis, diarrhoea, allergic

reactions including urticaria and pruritus, deficiency of available oxygen in the blood and bodily

tissues (hypoxia), back pain, abdominal pain and generally feeling unwell.

If any of the side effects gets serious, or if you notice any side effects not listed in this leaflet,

please tell your doctor or pharmacist.

Reporting of side effects

If you get any side effects talk to your doctor, pharmacist or nurse. This includes any possible

side effects not listed in this leaflet. You can also report side effects directly via:

UK: Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

ROI: HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax:

+353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

By reporting side effects you can help provide more information on the safety of this medicine.

5. How to store Bramitob

Keep this medicine out of the sight and reach of children

For single use only. Do not use Bramitob after the expiry date which is stated on the

outer pack and label after EXP. The expiry date refers to the last day of that month. You

can use Bramitob also if the colour of the solution varies.

In use shelf life: Bramitob bags (intact or opened) may be stored for up to 3 months at not

more than 25ºC.

Store in a refrigerator (2-8ºC). You can store the single-dose container for up to 3 months

at not more than 25ºC., if you don’t have a refrigerator available and for transporting

purposes.

Store your containers in the original packaging in order to protect from light.

After first opening the single-dose container: Use immediately.

After first use: Discard the used single-dose container immediately.

Do not throw away any medicines via wastewater or household waste. Ask your

pharmacist how to throw away medicines you no longer use. These measures will help to

protect the environment.

6. Contents of the pack and other information

What Bramitob contains

The active substance is tobramycin. Each 4ml single-dose container contains tobramycin

300 mg.

The other ingredients are sodium chloride, sulphuric acid and sodium hydroxide (for pH

adjustment), water for injections.

What Bramitob looks like and contents of the pack

Bramitob appears as a clear, yellowish solution.

Your Bramitob Nebuliser Solution comes in 4ml single-dose containers. There are 4 containers

in each sealed bag, in box sizes of 4, 16, 28 or 56.

Not all pack sizes may be marketed.

Marketing Authorisation Holder and Manufacturer

Marketing Authorisation Holder:

Chiesi Limited, 333 Styal Road, Manchester, M22 5LG, United Kingdom.

Manufacturer: Chiesi Farmaceutici S.p.A, 26/A Via Palermo, 43122 Parma, Italy or

Genetics S.p.A., Contradad Canfora, 84084 Fisciano (Italy)

This medicinal product is authorised in the Member States of the EEA under the following

names:

Austria: Bramitob

Netherlands: Bramitob

Czech Republic: Bramitob

Poland: Bramitob

Germany: Bramitob

Portugal: Bramitob

Greece: Bramitob

Slovak Republic: Bramitob

Hungary: Bramitob

Spain: Bramitob

Ireland: Bramitob

United Kingdom: Bramitob

Italy: Tobrineb

Is this leaflet hard to see or read? Phone for help: 0161 488 5555 (from UK)

+44161 488 5555 (from Ireland)

This leaflet was last revised in 02/2019

CP0005/10

CHIESI ITEM

CHIESI FARMACEUTICI S.p.A. - Parma - Italy

NOT TO TAMPER THIS DOCUMENT

Artwork Owner: MS- mail: m.sigurani@chiesi.com

Black + halft...%

I certify here by under my personal responsibility that the signed text is in full compliance with the official version approved

by the relevant regulatory Authority and in agreement with all regulations in force in the country, where the product will be

distributed.

Approved & Proceed

JOB TITLE:

Name (in capital letter):

Signature:

Date:

Amend & Re-Submit

APPROVAL MOCK UP

Name:

Date:

CHECK BY

28/02/19

PROOF N. / DATE

FROM: /CHANGE FOR

BRAMITOB 300mg 4ml sol. da neb. CH. LTD

/

F049

150 x 500 mm (Folding 150 x 62,5 mm)

Arial 8,5 pt

DIECUT

DESCRIPTION OF MATERIAL:

CODE MOCK UP:

FORMAT:

DIMENSIONS mm:

FONT AND min. SIZE:

REF. STD VARNISH:

COLOUR PRINT N.: 1

Reason of the change:

Text for SUBMISSION: National Phase Type II Local Approval

Text received on 26/02/2019 From: Ch.Ltd

1

01/03/19

2

CH.Ltd: text correction

01/03/19

3

CH.Ltd: text correction

BACK

PAG. 2/2

Health Products Regulatory Authority

09 April 2019

CRN008JR8

Page 1 of 8

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

Bramitob 300mg/4ml Nebuliser Solution

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 4 ml single-dose container contains tobramycin 300 mg.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Nebuliser solution.

Clear, yellowish solution.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

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

older.

4.2 Posology and method of administration

Bramitob 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 Bramitob,

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 Bramitob 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 (see section 4.4).

Patients with renal impairment

Tobramycin should be used with caution in patients with known or suspected renal, dysfunction. Bramitob should be

discontinued in the case of nephrotoxicity until serum concentration of tobramycin fall below 2 µg/mL (see section 4.4).

Patients with hepatic insufficiency

No changes in Bramitob dose are required in hepatic insufficiency.

Dosage is not adjusted for body weight. All patients should be administered one single-dose container of Bramitob (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 Bramitob 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.

Health Products Regulatory Authority

09 April 2019

CRN008JR8

Page 2 of 8

Administration of Bramitob 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 Bramitob 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)

Bramitob 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 Bramitob.

Bramitob should not be mixed with other inhalation medicinal products.

4.3 Contraindications

Administration of Bramitob is contraindicated in all patients with hypersensitivity to tobramycin, to any other aminoglycosides

or to any of the excipients listed in section 6.1. It is also contraindicated in patients receiving potent diuretics, such as

furosemide or ethacrynic acid, which have proved to be ototoxic.

4.4 Special warnings and precautions for use

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 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 Bramitob should be given under medical supervision, using a pre-nebulisation bronchodilator if this is already part

of the current treatment regimen for the patient. FEV

(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, Bramitob 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.

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09 April 2019

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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, eg 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, ie 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 particularly 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 Bramitob. 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 Bramitob 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. There is a theoretical risk that patients being treated with nebulised

tobramycin may develop P. aeruginosa isolates resistant to intravenous tobramycin (see section 5.1 Pharmacodynamic

properties). In clinical trials there is no data in patients with Burkholderia cepacia infections.

For information related to administration during pregnancy and lactation see section 4.6 “Fertility, Pregnancy and lactation”.

4.5 Interaction with other medicinal products and other forms of interactions

Concurrent and/or sequential use of Bramitob with other medicinal products with nephrotoxic or ototoxic potential should be

avoided. Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue.

Bramitob should not be administered concomitantly with furosemide, ethacrynic acid, urea or intravenous and oral - mannitol.

Other medicinal products that have been reported to increase the potential toxicity of parenterally administered

aminoglycosides include:

Health Products Regulatory Authority

09 April 2019

CRN008JR8

Page 4 of 8

amphotericin B, cephalotin, ciclosporin, tacrolimus, polymyxins (risk of increased nephrotoxicity); platinium compounds (risk

increased nephrotoxicity and ototoxicity) anticholinesterases, botulinum toxin: Due to their neuromuscular effects, the

combination with tobramycin should be avoided.

In clinical studies, patients taking nebulised tobramycin concomitantly with dornase alfa, mucolytic, B agonists, inhaled

corticosteroids, and other oral or parenteral anti-pseudomonal antibiotics, showed adverse events similar to the patients of the

control group.

4.6 Fertility, pregnancy and lactation

Bramitob should not be used during pregnancy or lactation unless the benefits to the mother outweigh the risks to the fetus or

baby.

Pregnancy

There are no adequate data from the use of tobramycin administered by inhalation in pregnant women. Animal studies do not

indicate a teratogenic effect of tobramycin (see section 5.3 Preclinical data). However, aminoglycosides can cause fetal harm

(e.g., congenital deafness) when high systemic concentrations are achieved in a pregnant woman. If Bramitob is used during

pregnancy, or if the patient becomes pregnant while taking Bramitob, she should be informed of the potential hazard to the

fetus.

Lactation

Systemic tobramycin is excreted in breast milk. It is not known if inhaled tobramycin will result in serum concentrations high

enough for tobramycin to be detected in breast milk. Because of the potential risk for ototoxicity and nephrotoxicity with

tobramycin in infants, a decision should be made whether to terminate nursing or discontinue Bramitob therapy.

4.7 Effects on 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 the 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.

4.8 Undesirable effects

In controlled clinical trials (4) and uncontrolled clinical trials (1) with Bramitob (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).

System Organ Class

Adverse Reaction

Frequency

Infections & Infestations

Fungal infection, oral candidiasis

Uncommon

Nervous system disorders

Headache

Uncommon

Ear and labyrinth disorders

Vertigo, hypoacusis, deafness neurosensory (see section

4.4)

Uncommon

Respiratory, thoracic and mediastinal disorders

Cough, dysphonia

Common

Forced expiratory volume decreased, dyspnoea, rales,

haemoptysis, oropharyngeal pain, productive cough

Uncommon

Gastrointestinal disorders

Salivary hypersecretion, glossitis, abdominal pain upper,

nausea

Uncommon

Skin and subcutaneous tissue disorders

Rash

Uncommon

General disorders and administration site conditions

Asthenia, chest discomfort, mucosal dryness

Uncommon

Investigations

Transaminases increased

Uncommon

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

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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):

System Organ Class

Adverse Reaction

Frequency

Infections & Infestations

Laryngitis

Rare

Fungal infection, oral candidiasis

Very rare

Blood and lymphatic system disorders

Lymphadenopathy

Very rare

Immune system disorders

Hypersensitivity

Very rare

Metabolism and nutrition disorders

Anorexia

Rare

Nervous system disorders

Dizziness, headache, aphonia

Rare

Somnolence

Very rare

Ear and labyrinth disorders

Tinnitus, hearing loss (see section 4.4)

Rare

Ear disorders, ear pain

Very rare

Respiratory, thoracic and mediastinal disorders

Cough, pharyngitis, dysphonia, dyspnoea

Uncommon

Bronchospasm, chest discomfort, lung disorder,

haemoptysis, epistaxis, rhinitis, asthma, productive

cough

Rare

Hyperventilation, hypoxia, sinusitis

Very rare

Gastrointestinal disorders

Dysgeusia, mouth ulceration, vomiting, nausea

Rare

Diarrhoea, abdominal pain

Very rare

Skin and subcutaneous tissue disorders

Rash

Rare

Urticaria, pruritus

Very rare

Musculo-skeletal, connective tissue and bone disorders

Back pain

Very rare

General disorders and administration site conditions

Asthenia, pyrexia, chest pain, pain, nausea

Rare

Malaise

Very rare

Investigations

Pulmonary function test decreased

Rare

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 sections 4.3

“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 HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971; Fax: +353 1 6762517. Website:

www.hpra.ie; E-mail: medsafety@hpra.ie.

4.9 Overdose

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 Bramitob, toxicity is unlikely as tobramycin is poorly absorbed from an intact

gastrointestinal tract. In the event of inadvertent intravenous administration of Bramitob, 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.

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Treatment

Acute toxicity should be treated with immediate withdrawal of Bramitob, 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 Bramitob or other medicinal products should be considered.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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:

Susceptible

Pseudomonas aeruginosa

Haemophilus influenzae

Staphylococcus aureus

Insusceptible Burkholderia cepacia

Stenotrophomonas maltophilia

Alcaligenes xylosoxidans

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 Bramitob 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

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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.

5.2 Pharmacokinetic properties

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 Bramitob, 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 Bramitob 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

Bramitob 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.

5.3 Preclinical safety data

In repeated dose toxicity studies, the target organs are the kidneys and vestibular/cochlear functions. In general, the signs and

symptoms of nephrotoxicity and ototoxicity are seen at higher systemic tobramycin levels than are achievable by inhalation at

the recommended clinical dose.

In preclinical studies, administration of inhaled tobramycin during up to 28 consecutive days determined modest, unspecific

and fully reversible (on therapy discontinuation) signs of irritation in the respiratory tract, and signs of renal toxicity, at the

highest doses.

No reproductive toxicology studies have been carried out with inhaled tobramycin, but subcutaneous administration of doses

up to 100mg/kg/day during organogenesis in rats was not teratogenic. In rabbits, subcutaneous administration of doses of

20-40mg/kg caused maternal toxicity and abortions, but without evidence of any teratogenic signs. Considering the data

available from animals, a risk of toxicity (e.g. ototoxicity) at prenatal exposure levels cannot be excluded. Tobramycin was not

shown to be genotoxic.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium chloride

Sulphuric acid

Sodium hydroxide

Water for injections

6.2 Incompatibilities

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

nebuliser.

6.3 Shelf life

2 years.

After first opening the single-dose container: use immediately.

In use shelf life: Bramitob bags (intact or opened) may be stored for up to 3 months at not more than 25

6.4 Special precautions for storage

Store in a refrigerator (2-8°C).

Store in the original package in order to protect from light.

The solution of Bramitob single-dose container is normally yellowish; some variations in colour might be observed, which does

not indicate any loss of activity if the product has been stored as recommended.

6.5 Nature and contents of container

The medicinal product is supplied in 4ml single-dose polyethylene containers, in sealed foiled bags each holding 4 single-dose

containers.

Pack sizes: 4, 16, 28 or 56 single-dose containers

Not all pack sizes may be marketed.

6.6 Special precautions for disposal of a used medicinal product or waste materials derived from such medicinal

product and other handling of the product

For single use only.

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

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

7 MARKETING AUTHORISATION HOLDER

Chiesi Limited,

Cheadle Royal Business Park,

Highfield,

Cheadle,

SK8 3GY

United Kingdom

8 MARKETING AUTHORISATION NUMBER

PA0743/017/001

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 1

June 2007

Date of last renewal: 23 March 2011

10 DATE OF REVISION OF THE TEXT

April 2019

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