Consumer medicine information

Tobramycin WKT

Tobramycin

BRAND INFORMATION

Brand name

Tobramycin WKT

Active ingredient

Tobramycin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Tobramycin WKT.

SUMMARY CMI

TOBRAMYCIN WKT

Consumer Medicine Information (CMI) summary

The full CMI on the next page has more details. If you are worried about using this medicine, speak to your doctor or pharmacist.

1. Why am I using TOBRAMYCIN WKT?

TOBRAMYCIN WKT contains the active ingredient tobramycin. Tobramycin is antibacterial agent, which is active against a common lung infection that occurs in patients with cystic fibrosis (CF).

For more information, see Section 1. Why am I using TOBRAMYCIN WKT? in the full CMI.

2. What should I know before I use TOBRAMYCIN WKT?

Do not use if you have ever had an allergic reaction to tobramycin or any of the ingredients listed at the end of the CMI.

Talk to your doctor if you have any other medical conditions, take any other medicines, or are pregnant or plan to become pregnant or are breastfeeding.

For more information, see Section 2. What should I know before I use TOBRAMYCIN WKT? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with TOBRAMYCIN WKT and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use TOBRAMYCIN WKT?

  • Inhale TOBRAMYCIN WKT as prescribed by your doctor. Breathe normally through the mouthpiece of the nebuliser until all of the solution is gone and there is no mist being produced.
  • The recommended dose of TOBRAMYCIN WKT is one ampoule twice daily for 28 days, followed by 28 days of not taking TOBRAMYCIN WKT. Repeat the 28 day on drug/28 day off drug cycle.

More instructions can be found in Section 4. How do I use TOBRAMYCIN WKT? in the full CMI.

5. What should I know while using TOBRAMYCIN WKT?

Things you should do
  • Remind any doctor, dentist or pharmacist you visit that you are using TOBRAMYCIN WKT inhaler.
  • Tell your doctor if you are pregnant, intend to become pregnant, are breast feeding or plan to breast-feed.
  • Tell your doctor if you have any other medical conditions.
  • If you plan to have surgery with a general anaesthetic, tell your doctor /dentist that you are using TOBRAMYCIN WKT
Things you should not do
  • Do not use this medicine if the solution is cloudy or if there are particles in the solution.
  • Do not use any TOBRAMYCIN WKT which has been stored at room temperature for more than 28 days.
  • Do not dilute or mix other medications with TOBRAMYCIN WKT in the nebuliser.
  • Never use a dirty or clogged nebulizer and do not share your nebuliser with other people.
  • Do not give TOBRAMYCIN WKT to anyone else, or use it to treat any other complaints.
  • Do not stop using TOBRAMYCIN WKT or lower the dosage, without checking with your doctor or pharmacist.
Driving or using machines
  • Be careful driving or operating machinery until you know how TOBRAMYCIN WKT affects you.
  • TOBRAMYCIN WKT may cause dizziness, ringing in the ears, or light-headedness in some people.
Drinking alcohol
  • If you drink alcohol, you may experience dizziness or light-headedness.
Looking after your medicine
  • Store TOBRAMYCIN WKT between 2-8°C in the refrigerator. Opened ampoules must be used immediately.
  • You can store the foil pouches (opened or unopened) at room temperature (up to 25°C) for up to 28 days.

For more information, see Section 5. What should I know while using TOBRAMYCIN WKT? in the full CMI.

6. Are there any side effects?

Common side effects include: runny or stuffy nose, sneezing, voice alteration, loss of voice, difficulty swallowing (laryngitis), discoloured substance you cough up (sputum), decreased lung function test results, muscle pain, generally feeling unwell, itching or itchy rash, sore throat, disturbed sense of taste, anorexia, vomiting, nausea, diarrhoea, digestive changes, yeast mouth infection, sweating.

Serious side effects include: ringing, noises (such as hissing) or pain in the ears, hearing loss, dizziness, light-headedness, clumsiness, lack of coordination, chest pain or tightness, increased coughing, wheezing or difficulty in breathing, generally feeling unwell, discolored sputum, diarrhoea or abdominal pain, even several weeks after use, worsening of your lung disease. Signs of an allergic reaction include: swelling of the face, lips, mouth, throat or tongue, difficulty in swallowing or breathing, shortness of breath, skin rash, wheezing or coughing or chest tightness.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.



FULL CMI

TOBRAMYCIN WKT

Active ingredient: tobramycin

Consumer Medicine Information (CMI)

This leaflet provides important information about using TOBRAMYCIN WKT. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about using TOBRAMYCIN WKT.

Where to find information in this leaflet:

1. Why am I using TOBRAMYCIN WKT?
2. What should I know before I use TOBRAMYCIN WKT?
3. What if I am taking other medicines?
4. How do I use TOBRAMYCIN WKT?
5. What should I know while using TOBRAMYCIN WKT?
6. Are there any side effects?
7. Product details

1. Why am I using TOBRAMYCIN WKT?

TOBRAMYCIN WKT contains the active ingredient tobramycin. Tobramycin belongs to a class of antibiotics called aminoglycosides. It works by killing or stopping the growth of the bacteria that cause infection. The bacterium that commonly infects the lung of most cystic fibrosis patients at some stage of their lives is Pseudomonas aeruginosa. It is one of the most damaging bacteria for people with CF.

TOBRAMYCIN WKT contains an antibacterial agent which is active against a common lung infection that occurs in patients with cystic fibrosis (CF).

If the infection is not properly fought, it will continue to damage your lungs, causing further problems with your breathing.

TOBRAMYCIN WKT solution has been specially formulated for administration by inhalation via a nebuliser and compressor. When you inhale TOBRAMYCIN WKT the antibiotic can get straight into your lungs to fight against the infection and to improve your breathing.

Although TOBRAMYCIN WKT does not cure your condition, it does help control it. TOBRAMYCIN WKT is not recommended for use in children younger than 6 years of age.

2. What should I know before I use TOBRAMYCIN WKT?

Warnings

Do not use TOBRAMYCIN WKT if:

  • you are allergic to tobramycin, or any antibiotics that belong to the aminoglycoside group (e.g. amikacin, gentamicin, neomycin, or streptomycin), or any of the ingredients listed at the end of this leaflet.

Always check the ingredients to make sure you can use this medicine.

The symptoms of an allergic reaction may include: skin rash, itchiness, shortness of breath, wheezing or difficulty breathing, swelling of the lips, tongue, face or other parts of the body.

Do not give TOBRAMYCIN WKT to a child below the age of 6, unless directed to by the child's doctor or pharmacist.

TOBRAMYCIN WKT is not recommended for use in children under 6 years.

Check with your doctor if you:

  • have kidney problems
  • have hearing problems, including noises in the ears and dizziness
  • have unusual difficulty in breathing with wheezing or coughing, chest tightness
  • have trouble with your balance or dizzy spells
  • have problems with nerve or muscle function
  • have muscle weakness that lasts, or becomes worse in time, a symptom mostly related to conditions such as Parkinson's disease (a brain condition affecting movement)
  • have myasthenia (a condition in which the muscles become weak and tire easily).
  • have any other medical conditions
  • take any medicines for any other condition
  • have allergies to any other medicines, substance or foods
  • are aged 65 years or older, as your doctor may perform additional tests to decide if TOBRAMYCIN WKT is right for you.

During treatment, you may be at risk of developing certain side effects. It is important you understand these risks and how to monitor for them. See additional information under Section 6. Are there any side effects?

Pregnancy and breastfeeding

Check with your doctor if you are pregnant or intend to become pregnant.

TOBRAMYCIN WKT may affect your developing baby if you use it during pregnancy. Your doctor or pharmacist will discuss the possible risks and benefits of using TOBRAMYCIN WKT during pregnancy.

Talk to your doctor if you are breastfeeding or intend to breastfeed.

Your baby may absorb this medicine from breast milk and therefore there is a possibility of harm to the baby. Your doctor or pharmacist will discuss the risks and benefits of using TOBRAMYCIN WKT during breast-feeding.

3. What if I am taking other medicines?

Tell your doctor or pharmacist if you are taking any other medicines, including any medicines, vitamins or supplements that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and TOBRAMYCIN WKT may interfere with each other. These include:

  • diuretics (fluid tablets), especially those that contain frusemide, or ethacrynic acid
  • urea
  • intravenous mannitol
  • tobramycin or another aminoglycoside antibiotic by injection (e.g. amikacin, gentamicin, neomycin, streptomycin)

Check with your doctor or pharmacist if you are not sure about what medicines, vitamins or supplements you are taking and if these affect TOBRAMYCIN WKT.

4. How do I use TOBRAMYCIN WKT?

How much to use

  • Inhale TOBRAMYCIN WKT only when prescribed by your doctor.
  • Do not exceed the recommended dose. The recommended dose of TOBRAMYCIN WKT is one 300 mg/5 mL ampoule twice daily (every 12 hours) for 28 days.
  • This is followed by 28 days of not taking TOBRAMYCIN WKT.
  • Repeat the 28 day on drug/28 day off drug cycle.
  • Follow all directions given to you by your doctor and pharmacist carefully. They may differ from the information contained in this leaflet.
  • If you do not understand the instructions on the carton or leaflet, ask your doctor or pharmacist for help.
  • TOBRAMYCIN WKT solution is contained in a ready-to-use ampoule and is specifically formulated for inhalation therapy using a PARI LC PLUS reusable nebuliser and a compressor. It is important that your nebuliser and compressor function properly before you start your TOBRAMYCIN WKT therapy.
  • Breathe normally through the mouthpiece of the nebuliser until all of the TOBRAMYCIN WKT solution is gone and there is no longer any mist being produced. This is usually for a period of approximately 15 minutes. You may sit or stand upright while inhaling your dose.
  • If you are not sure how to use a nebuliser, ask your doctor or pharmacist. Children should only use a nebuliser on medical advice and with the help of an adult.

When to use TOBRAMYCIN WKT

  • If you are taking several different inhaled treatments and performing therapies for cystic fibrosis, you should use TOBRAMYCIN WKT last.
  • Use TOBRAMYCIN WKT at about the same time every day. Using your medicine at the same time each day will help you remember when to take it.
  • Inhale TOBRAMYCIN WKT twice daily.
  • Doses should be administered as close to 12 hours apart as possible and not less than 6 hours apart.

How to inhale TOBRAMYCIN WKT

  1. Wash your hands thoroughly with soap and water and fully dry hands.
  2. Just before use, cut or tear open the foil pouch and remove one TOBRAMYCIN WKT ampoule by gently pulling apart one of the attached ampoules at the bottom tabs.
  3. Put the other ampoule(s)back in the foil pouch and keep it in the refrigerator.
  4. Layout all the pieces of your nebuliser on a clean, dry paper or cloth towel:
    a. nebuliser top
    b. nebuliser cup
    c. inspiratory valve cap
    d. mouthpiece with valve tubing
  5. Check that you have the suitable compressor, and tubing to connect the nebuliser and compressor.
  6. Follow the appropriate instructions for use for your type of nebuliser. You must read the leaflet provided with the nebuliser by the manufacturer.
  7. Check that your nebuliser and compressor are working properly according to the manufacturer's instructions before you start to take your medicine.
  8. Remove the nebuliser top from the nebuliser cup by twisting the top anticlockwise and then lifting it.
  9. Place the nebuliser top on the towel and stand the nebulizer cup upright on the towel.
  10. Connect one end of the tubing to the compressor air outlet. Make sure that the tubing fits snugly. Plug the compressor into the electrical outlet.
  11. Open the TOBRAMYCIN WKT ampoule by holding the bottom tab with one hand and twisting off the top with your other hand.
  12. Squeeze all the contents of the ampoule into the nebuliser cup.
  13. Replace the nebuliser top (a), put the mouthpiece (d) and the inspiratory valve cap (c) in place on the nebuliser, and then connect the compressor as indicated in your nebuliser leaflet.
  14. Turn on the compressor. Check that there is a steady mist coming from the mouthpiece. If there is no mist, check all tubing connections and that the compressor is working properly.
  15. Sit or stand in an upright position so that you can breathe normally.
  16. Place the mouthpiece between your teeth and on top of your tongue. Breathe normally, but only through your mouth (you may use a nose clip if your doctor agrees). Try not to block the air flow with your tongue.
  17. Continue until all of the TOBRAMYCIN WKT solution is gone and there is no longer any mist being produced. It should take about 10-15 minutes to inhale all of the treatment. You may hear a spluttering sound when the nebuliser cup is empty.
  18. Clean, disinfect, and dry your nebuliser after each use, according to the manufacturer's instructions. It may not work as well if it gets dirty.

If you forget to use TOBRAMYCIN WKT

If there are at least 6 hours to your next dose, use TOBRAMYCIN WKT and then go back to using your medicine as you would normally.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

Do not take a double dose to make up for the dose you missed. This may increase the chance of you getting any unwanted side effects.

If you are not sure whether to skip the dose, talk to your doctor or pharmacist.

If you use too much TOBRAMYCIN WKT

If you think that you have used too much TOBRAMYCIN WKT, you may need urgent medical attention.

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26); or
  • contact your doctor; or
  • go to the Emergency Department at your nearest hospital.

You should do this even if there are no signs of discomfort or poisoning.

Signs of an overdose may include:

  • loss of balance
  • hearing problems
  • breathing problems
  • kidney problems
  • difficulty with nerve and muscle function
  • dizziness
  • ringing in the ears

5. What should I know while using TOBRAMYCIN WKT?

Things you should do

Keep TOBRAMYCIN WKT in the foil pouch (opened or unopened) in the pack until it is time for your dose. If you take the medication out of the pouch it will not keep well. TOBRAMYCIN WKT is sensitive to very strong light.

Consult the package insert supplied with TOBRAMYCIN WKT for detailed information and diagrams describing the correct use and care of your inhalation equipment and instructions on how to use TOBRAMYCIN WKT.

If you are interrupted, or need to cough or rest during your TOBRAMYCIN WKT treatment, turn off the compressor to save your medicine. Turn the compressor on again when you are ready to restart your treatment.

If you become pregnant while using TOBRAMYCIN WKT tell your doctor immediately.

Tell any other doctors, dentists, and pharmacists who are treating you that you are using TOBRAMYCIN WKT.

If you are about to be started on any new medicine, tell your doctor, dentist or pharmacist that you are using TOBRAMYCIN WKT.

If you plan to have surgery that needs a general anaesthetic, tell your doctor or dentist that you are using TOBRAMYCIN WKT.

Things you should not do

  • Do not use this medicine if the solution is cloudy or if there are particles in the solution.
  • Do not use any TOBRAMYCIN WKT which you have stored at room temperature for more than 28 days.
  • Do not dilute or mix other medications, with TOBRAMYCIN WKT in the nebuliser.
  • Never use a dirty or clogged nebuliser.
  • Do not share your nebuliser with other people.
  • Do not give TOBRAMYCIN WKT to anyone else, even if they have the same condition as you.
  • Do not use TOBRAMYCIN WKT to treat any other complaints unless your doctor tells you to.
  • Do not stop using TOBRAMYCIN WKT or lower the dosage, without checking with your doctor or pharmacist.

Things to be careful of

  • Inhaling medicines can cause chest tightness and wheezing. This may happen immediately after inhaling this medicine.
  • If you have swallowed TOBRAMYCIN WKT in error, tell your doctor as soon as possible.
    When swallowed, this medicine will not harm you, but this medicine will not work as it is meant to.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how TOBRAMYCIN WKT affects you.

TOBRAMYCIN WKT may cause dizziness, ringing in the ears, or light-headedness in some people.

If you feel dizzy or light-headed after using TOBRAMYCIN WKT do not drive, operate machinery, use tools, or do anything else that could be dangerous if you are dizzy or lightheaded.

Drinking alcohol

Tell your doctor if you drink alcohol.

If you drink alcohol, you may experience dizziness or light-headedness.

Looking after your medicine

Store TOBRAMYCIN WKT between 2-8°C in the refrigerator.

If you do not have a refrigerator available (e.g. when transporting TOBRAMYCIN WKT), you can store the foil pouches (opened or unopened) at room temperature (up to 25°C) for up to 28 days.

Do not store any opened ampoules of TOBRAMYCIN WKT

Once opened, the solution should be used immediately.

Store it in a cool dry place away from moisture, heat or sunlight; for example, do not store it:

  • in the bathroom or near a sink; or
  • in the car or on window sills.

Keep it where young children cannot reach it.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

See the information below and, if you need to, ask your doctor or pharmacist if you have any further questions about side effects.

Less serious side effects

Less serious side effectsWhat to do
  • Runny or stuffy nose, sneezing
  • voice alteration, loss of voice
  • sore throat
  • difficulty swallowing (laryngitis)
  • discolouration of the substance you cough up (sputum)
  • decreased lung functions test results
  • muscle pain
  • generally feeling unwell
  • itching or itchy rash
  • disturbed sense of taste
  • anorexia, vomiting, nausea, diarrhoea, digestive changes, yeast mouth infection
  • sweating
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
  • ringing in the ears or hearing loss
  • noises in the ears (such as hissing) or pain
  • dizziness
  • light-headedness
  • clumsiness or lack of coordination
  • chest pain or chest tightness
  • increased coughing, wheezing or difficulty in breathing
  • generally feeling unwell
  • discoloration of the substance you cough up (sputum)
  • diarrhoea or abdominal pain, even several weeks after use

Signs of an allergic reaction, including:

  • swelling of the face, lips, mouth, throat or tongue, difficulty in swallowing or breathing
  • shortness of breath
  • skin rash
  • unusual difficulty in breathing, with wheezing, coughing or chest tightness
  • worsening of your underlying lung disease.
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

If you are taking tobramycin or another aminoglycoside antibiotic by injection, it may sometimes cause hearing loss, dizziness, and kidney damage, and may harm an unborn child.

Tell your doctor or pharmacist if you notice anything else that may be making you feel unwell.

Other side effects not listed here may occur in some people.

Reporting side effects

After you have received medical advice for any side effects you experience, you can report side effects to the Therapeutic Goods Administration online at www.tga.gov.au/reporting-problems. By reporting side effects, you can help provide more information on the safety of this medicine.

Always make sure you speak to your doctor or pharmacist before you decide to stop taking any of your medicines.

7. Product details

This medicine is only available with a doctor's prescription. It is not addictive.

Each 5 mL single dose ampoule contains tobramycin 300 mg.

What TOBRAMYCIN WKT contains

Active ingredient
(main ingredient)		tobramycin
Other ingredients
(inactive ingredients)
  • sodium chloride
  • water for injections
  • nitrogen
  • sulfuric acid#
  • sodium hydroxide#

#These ingredients may have been added to adjust the pH of the final solution.

Do not take this medicine if you are allergic to any of these ingredients.

TOBRAMYCIN WKT does not contain preservatives, lactose, sucrose, gluten, tartrazine or any other azo dyes.

What TOBRAMYCIN WKT looks like

Each carton of TOBRAMYCIN WKT contains 56 single-dose ampoules (a 28-day supply). The ampoules are in 8 pouches with 7 ampoules in each pouch.

TOBRAMYCIN WKT is supplied in clear, single-use low density polyethylene ampoules that are packaged in foil pouches. The solution is clear and particle free. (AUST R 279353).

Who distributes TOBRAMYCIN WKT

Luminarie Pty Ltd
Level 5, 4 Columbia Ct,
BAULKHAM HILLS NSW 2153

This leaflet was prepared in December 2023.

Published by MIMS February 2024

BRAND INFORMATION

Brand name

Tobramycin WKT

Active ingredient

Tobramycin

Schedule

S4

 

1 Name of Medicine

Tobramycin.

2 Qualitative and Quantitative Composition

Tobramycin WKT solution for inhalation is formulation of tobramycin specifically developed for administration by inhalation.
Tobramycin WKT solution is a sterile, clear, slightly yellow, non-pyrogenic, aqueous solution with the pH and salinity adjusted specifically for administration by a compressed air driven reusable nebuliser.
Each Tobramycin WKT solution single-use 5 mL ampoule contains 300 mg tobramycin and 11.25 mg sodium chloride in sterile water for injections. Sulfuric acid and sodium hydroxide are added to adjust the pH to 6.0. Nitrogen is used for sparging. All ingredients meet Ph Eur. requirements. The formulation contains no preservatives.

3 Pharmaceutical Form

See Section 2 Qualitative and Quantitative Composition.

4 Clinical Particulars

4.1 Therapeutic Indications

Tobramycin WKT solution is indicated for the management of cystic fibrosis patients with P. aeruginosa infections.
Safety and efficacy have not been demonstrated in patients under the age of 6 years, patients with FEV1 ≤ 25% or ≥ 80% predicted at screening, or patients colonized with Burkholderia cepacia (see Section 5.1 Pharmacodynamic Properties, Clinical trials).

4.2 Dose and Method of Administration

Dosage.

Dosage is not adjusted by age or weight. The doses should be taken as close to 12 hours apart as possible; they should not be taken less than six hours apart. In case of a 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 medication to make up for the missed dose.
Tobramycin WKT solution is administered twice daily in alternating periods of 28 days. After 28 days of therapy, patients should stop therapy for the next 28 days, and then resume therapy for the next 28 day on/28 day off cycle.
Therapy should be initiated by a physician experienced in the management of cystic fibrosis. Treatment with tobramycin solution 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 tobramycin solution in their treatment regimen. If clinical deterioration of pulmonary status is evident, additional anti-pseudomonal therapy should be considered.
Adults and paediatric patients 6 years of age and older. The recommended dosage for both adults and paediatric patients 6 years of age and older is one single use ampoule (300 mg) administered twice daily for 28 days.
Dosing in special populations.

Paediatric population below 6 years.

Tobramycin solution has not been studied and is not indicated for use in paediatric patients less than 6 years of age. Clinical studies with tobramycin solution have included children aged 6 years and above (see Section 5 Pharmacological Properties).

Elderly patients (≥ 65 years).

There are insufficient data in this population to support a recommendation for or against dose adjustment. Renal function in elderly patients should be taken into account while using tobramycin solution (see Section 4.4 Special Warnings and Precautions for Use).

Patients with renal impairment.

Patients with serum creatinine 153 mmol/L or more and blood urea nitrogen (BUN) 14 mmol/L 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 tobramycin solution. (See Section 4.4 Special Warnings and Precautions for Use).

Patients with hepatic impairment.

No studies have been performed on patients with hepatic impairment. As tobramycin is not metabolized, 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 in patients after organ transplantation.

Administration.

Where patients are receiving several different inhaled medications and performing chest physiotherapy, it is recommended that tobramycin is taken last.
Tobramycin solution is supplied as a single-use, ready to use ampoule and is administered by inhalation, over an approximately 15 minute period, using a hand-held nebuliser and compressor. (See Section 4.4 Special Warnings and Precautions for Use).
Tobramycin solution should be inhaled whilst the patient is sitting or standing upright and breathing normally through the mouthpiece of the nebulizer. Nose clips may be used to help the patient breathe through the mouth.
Tobramycin solution should not be diluted or mixed with dornase alfa or other medications in the nebuliser. See Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.
During clinical studies, patients on multiple therapies were instructed to take them first, followed by tobramycin.
Detailed instructions for use are provided in the patient package insert supplied with tobramycin.

4.3 Contraindications

Tobramycin is contraindicated in patients with a known hypersensitivity to any aminoglycoside.

4.4 Special Warnings and Precautions for Use

Tobramycin solution is for oral inhalation only.
Tobramycin solution is not for subcutaneous, intravenous or intrathecal administration.
The use of Tobramycin WKT solution with nebulisers other than the Pari LC Plus reusable nebuliser or Pari Pro-neb system with a DeVilbiss Pulmo-Aide compressor has not been adequately studied.
Caution should be exercised when prescribing tobramycin solution to patients with known or suspected renal, auditory, vestibular, or neuromuscular dysfunction. Patients receiving concomitant parenteral aminoglycoside therapy should be monitored as clinically appropriate.
Aminoglycosides can cause foetal harm when administered to a pregnant woman. Aminoglycosides cross the placenta, and streptomycin has been associated with several reports of total, irreversible, bilateral congenital deafness in paediatric patients exposed in utero. Patients who use tobramycin solution during pregnancy, or become pregnant while taking one of these products should be apprised of the potential hazard to the foetus.

Ototoxicity.

In clinical studies, 4 patients (1%) reported mild to moderate hearing loss in clinical studies of up to 9 treatment cycles of tobramycin solution. Hearing loss was transient for 3 patients and ongoing at the end of study for one patient. Three of these patients had received IV aminoglycosides concomitantly to receiving tobramycin solution.
In post-marketing experience, some patients receiving tobramycin solution and extensive previous or concomitant parenteral aminoglycosides have reported hearing loss. Some of these reports occurred in patients with previous or concomitant treatment with systemic aminoglycosides. Patients with hearing loss frequently reported tinnitus. Tinnitus is a sentinel symptom of ototoxicity, and therefore the onset of this symptom warrants caution (see Section 4.8 Adverse Effects (Undesirable Effects)). Ototoxicity, manifested as both auditory and vestibular toxicity, has been reported with parenteral aminoglycosides. Vestibular toxicity may be manifested by vertigo, ataxia or dizziness.
Caution should be exercised when prescribing tobramycin solution to patients with known or suspected auditory or vestibular dysfunction. Physicians should consider an audiogram before initiating tobramycin therapy for patients who show any evidence of auditory dysfunction, or who are at increased risk for auditory dysfunction.
If a patient reports tinnitus or hearing loss during tobramycin solution therapy, the physician should refer them for audiological assessment.
If ototoxicity occurs in a patient receiving tobramycin solution, tobramycin therapy should be discontinued until tobramycin serum concentrations fall below 2 microgram/mL.

Risk of ototoxicity due to mitochondrial DNA variants.

Cases of ototoxicity with aminoglycosides have been observed in patients with certain variants in the mitochondrially encoded 12S rRNA gene (MT-RNRl), particularly the m.1555A>G variant. Ototoxicity occurred in some patients even when their aminoglycoside serum levels were within the recommended range. Mitochondrial DNA variants are present in less than 1% of the general US population, and the proportion of the variant carriers who may develop ototoxicity as well as the severity of ototoxicity is unknown. In case of known maternal history of ototoxicity due to aminoglycoside use or a known mitochondrial DNA variant in the patient, consider alternative treatments other than aminoglycosides unless the increased risk of permanent hearing loss is outweighed by the severity of infection and lack of safe and effective alternative therapies.

Nephrotoxicity.

Nephrotoxicity was not seen during tobramycin solution clinical studies but has been associated with aminoglycosides as a class. Nephrotoxicity has been reported with the use of parenteral aminoglycosides. Caution should be exercised when prescribing tobramycin solution to patients with known or suspected renal dysfunction.
If nephrotoxicity occurs in a patient receiving tobramycin solution, tobramycin therapy should be discontinued until tobramycin serum concentrations fall below 2 microgram/mL. Also see Section 4.4 Special Warnings and Precautions for Use.
Laboratory tests of renal function should be monitored as clinically appropriate. Urea and creatinine levels should be reassessed after every 6 complete cycles of therapy.

Neuromuscular dysfunction.

Tobramycin solution should be used cautiously in patients with muscular disorders, such as myasthenia gravis or Parkinson's disease, since aminoglycosides may aggravate muscle weakness because of a potential curare-like effect on neuromuscular function.

Bronchospasm.

Bronchospasm can occur with inhalation of medicinal products and has been reported with tobramycin solution. Bronchospasm should be treated as medically appropriate. If an allergic response is suspected, tobramycin solution should be discontinued.
In clinical studies of tobramycin, changes in FEV1 measured after the inhaled doses were similar in the tobramycin and placebo groups.

Cough.

Cough was the most commonly reported adverse event considered treatment related for tobramycin solution. If there is evidence of continued therapy-induced cough, the physician should consider the use of alternative therapeutic options.

Haemoptysis.

Haemoptysis is a complication in cystic fibrosis and is more frequent in adults. Patients with clinically significant haemoptysis (> 60 mL) were excluded from the clinical studies so no data exist on the use of tobramycin solution in these patients. The use of tobramycin solution in such patients should be undertaken only if the benefits of treatment are considered to outweigh the risks of inducing further haemorrhage.

Concomitant antibiotic therapy.

Serum concentrations of tobramycin 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, taking into account the risk of cumulative toxicity. See Section 4.4 Special Warnings and Precautions for Use.

Clostridium difficile-associated disease.

Antibiotic associated pseudomembranous colitis has been reported with many antibiotics including tobramycin. A toxin produced with Clostridioides difficile appears to be the primary cause. The severity of the colitis may range from mild to life threatening. It is important to consider this diagnosis in patients who develop diarrhoea or colitis in association with antibiotic use (this may occur up to several weeks after cessation of antibiotic therapy). Mild cases usually respond to drug discontinuation alone. However, in moderate to severe cases appropriate therapy with a suitable oral antibacterial agent effective against Clostridioides difficile should be considered. Fluids, electrolytes and protein replacement should be provided when indicated.

Use in hepatic impairment.

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

Use in renal impairment.

Tobramycin is primarily excreted unchanged in the urine and renal function is expected to affect the exposure to tobramycin. See Section 4.4 Special Warnings and Precautions for Use.

Use in the elderly.

See Section 5.2 Pharmacokinetic Properties, Characteristics in special populations, Elderly patients.

Paediatric use.

The safety and efficacy of tobramycin has not been studied in paediatric patients under 6 years of age.

Effects on laboratory tests.

Audiograms.

Tinnitus may be a sentinel symptom of ototoxicity, and therefore the onset of this symptom warrants caution. Physicians should consider an audiogram for patients who show any evidence of auditory dysfunction, or who are at increased risk for auditory dysfunction.

Serum concentrations.

In patients with normal renal function treated with tobramycin solution serum tobramycin concentrations are approximately 1 microgram/mL one hour after dose administration and do not require routine monitoring.
Serum concentrations of tobramycin 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, taking into account the risk of cumulative toxicity.
Serum concentrations of tobramycin should be monitored in patients with known or suspected auditory or renal dysfunction. Patients treated with concomitant parenteral tobramycin should be monitored at the discretion of the treating physician.
The serum concentration of tobramycin should only be monitored through venipuncture and not finger prick blood sampling. Contamination of the skin of the fingers with tobramycin may lead to falsely increased measurements of serum levels of the drug. This contamination cannot be completely avoided by hand washing before testing.

Renal function.

The clinical studies with tobramycin solution did not reveal any imbalance in the percentage of patients in the tobramycin and placebo groups who experienced at least a 50% rise in serum creatinine from baseline (see Section 4.8 Adverse Effects (Undesirable Effects)). Laboratory tests of urine and renal function should be conducted at the discretion of the treating physician.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No clinical drug interaction studies have been performed with tobramycin solution.
Some diuretics can enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. Tobramycin solution should not be administered concomitantly with ethacrynic acid, frusemide, urea, or intravenous mannitol.
Based on the interaction profile for tobramycin following intravenous and aerosolized administration, concurrent and/or sequential use of tobramycin solution with other drugs with neurotoxic, nephrotoxic, or ototoxic potential should be avoided.
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 tobramycin solution therapy.
Other medicinal products that have been reported to increase the potential toxicity of parenterally administered aminoglycosides include: amphotericin B, cefalotin, ciclosporin, tacrolimus, polymyxins (risk of increased nephrotoxicity); platinum compounds (risk of increased nephrotoxicity and ototoxicity); anticholinesterases, and botulinum toxin (neuromuscular effects).
Aminoglycosides may aggravate muscle weakness because of a potential curare-like effect on neuromuscular function.

Absence of interactions.

In clinical studies of tobramycin solution, patients taking tobramycin solution concomitantly with dornase alfa, β2-agonists, inhaled corticosteroids, other anti-pseudomonal antibiotics, or parenteral aminoglycosides demonstrated adverse experience profiles similar to the study population as a whole.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No reproduction toxicology studies have been conducted with tobramycin solution administered by inhalation.
Subcutaneous administration of up to 600 mg/m2/day of tobramycin did not affect mating behaviour or cause impairment of fertility in male or female rats, although fertility of the offspring was not examined.
(Category D)
There are no adequate data from the use of tobramycin administered by inhalation in pregnant women.
Subcutaneous administration of tobramycin at doses of 600 or 220 mg/m2/day during organogenesis was not teratogenic in rats or rabbits, respectively. Doses of tobramycin ≥ 440 mg/m2/day were severely maternally toxic to rabbits and precluded the evaluation of teratogenicity.
Aminoglycosides can cause foetal harm (e.g. congenital deafness) when administered to a pregnant woman and high systemic concentrations are achieved. Ototoxicity was not evaluated in offspring during nonclinical reproduction toxicity studies with tobramycin.
Treatment with tobramycin during pregnancy should be undertaken only if the benefits to the mother outweigh the risks to the foetus or baby. If tobramycin is used during pregnancy, or if the patient becomes pregnant while taking tobramycin, the patient should be apprised of the potential hazard to the foetus.
Aminoglycosides can cross the placenta. There is evidence of selective uptake of aminoglycosides by foetal kidney resulting in damage (probably reversible) to immature nephrons. Eighth cranial nerve damage has also been reported following in utero exposure to some of the aminoglycosides. Because of their chemical similarity, all aminoglycosides must be considered potentially nephrotoxic and ototoxic to the foetus. It should also be noted that therapeutic blood concentrations in the mother do not equate with safety to the foetus.
 It is not known if tobramycin will reach sufficient concentrations after administration by inhalation to be excreted in human breast milk. Because of the potential for ototoxicity and nephrotoxicity in infants, a decision should be made whether to terminate nursing or discontinue treatment with tobramycin, taking into account the importance of the drug to the mother.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.8 Adverse Effects (Undesirable Effects)

Adverse events in clinical trials.

Tobramycin solution. Tobramycin solution was generally well tolerated during two placebo-controlled clinical studies in 258 cystic fibrosis patients ranging in age from 6 to 48 years. Patients received tobramycin solution in alternating periods of 28 days on and 28 days off drug in addition to their standard cystic fibrosis therapy for a total of 24 weeks.
Voice alteration and tinnitus were the only adverse experiences reported by significantly more tobramycin solution-treated patients. Thirty-three patients (13%) treated with tobramycin solution complained of voice alteration compared to 17 (7%) placebo patients. Voice alteration was more common in the on-drug periods.
Eight patients from the tobramycin solution group (3%) reported tinnitus compared to no placebo patients. All episodes were transient, resolved without discontinuation of the tobramycin solution treatment regimen, and were not associated with loss of hearing in audiograms. Tinnitus is one of the sentinel symptoms of cochlear toxicity, and patients with this symptom should be carefully monitored for high frequency hearing loss. The numbers of patients reporting vestibular adverse experiences such as dizziness were similar in the tobramycin solution and placebo groups.
Nine (3%) patients in the tobramycin solution group and nine (3%) patients in the placebo group had increases in serum creatinine of at least 50% over baseline. In all nine patients in the tobramycin group, creatinine decreased at the next visit.
Table 1 lists the percent of patients with treatment-emergent adverse experiences that occurred in 25% of patients during the 48 weeks of the open label extension. The table also presents the corresponding data from the 24-week placebo-controlled studies, where one group of patients received placebo and the other group received tobramycin solution during the first three cycles of therapy.
Tobramycin capsules for inhalation dosage form. Tobramycin capsules for inhalation dosage form has been evaluated for safety in 395 CF patients exposed to at least one dose of tobramycin capsules for inhalation dosage form, including 273 who were exposed across three cycles (6 months) of treatment. Each cycle consisted of 28 days on treatment (with 112 mg administered twice daily) and 28 days off treatment. The majority of patients evaluated for safety were entered into Study C2302 which included an active-treatment control group administered tobramycin solution. The tobramycin capsules for inhalation dosage form group included 308 patients; the tobramycin solution group numbered 209 patients (see Section 5.1 Pharmacodynamic Properties, Clinical trials).
The primary safety population, randomized in a planned 3:2 ratio, consisted of the 308 patients treated with capsules for inhalation dosage form and 209 patients treated with tobramycin solution 300 mg/5 mL tobramycin nebulizer solution) in Study C2302, an open-label study comparing capsules for inhalation dosage form with tobramycin solution over 3 treatment cycles. For both treatment groups, mean exposure to medication for each cycle was 28-29 days.
The supportive safety population considered an additional 87 patients treated with capsules for inhalation dosage form and 49 treated with placebo in Study C2301, which was double-blind for the first treatment cycle, followed by all patients receiving capsules for inhalation dosage form for 2 additional cycles. At these exposures, capsules for inhalation dosage form were generally well tolerated.
In Study C2302, the most frequently occurring adverse drug reactions (ADRs) related to the respiratory, thoracic and mediastinal system organ class. The most commonly occurring ADRs (by preferred term) were cough and lung disorder in both the capsules for inhalation dosage form and tobramycin solution treatment groups.
During the placebo-controlled cycle of Study C2301, the overall incidence of ADRs was lower in the capsules for inhalation dosage form treatment group than in the placebo group, with the exceptions of pharyngolaryngeal pain, dysphonia, and dysgeusia.
In Study C2301, no patients reported adverse events related to hearing loss. Two patients were found during planned audiology testing to have significant decreases in hearing (defined as 10-15 dB in at least two consecutive frequencies, or 20 dB or more at a single frequency). In Study C2302, hearing complaints such as tinnitus were reported in approximately 2% of patients overall. Of a subset of patients in Study C2302 who received serial audiology testing, 25.6% (capsules for inhalation dosage form) and 15.6% (tobramycin solution) showed decreases from baseline at any visit (80% of the subset had normal hearing assessments at baseline). However, the majority of such changes was transient and had resolved by the end of the study. Four patients in the capsules for inhalation dosage form treatment group experienced significant decreases in hearing which were transient in three patients and persistent in one case. Less than 3% of patients in either group showed evidence of significant hearing loss. Using the criteria for either ear of 10 dB loss at 3 consecutive frequencies, 15 dB loss at two consecutive frequencies and 20 dB loss at any frequency, three capsules for inhalation dosage form patients and two tobramycin solution patients (matching the randomization ratio) were judged to have ototoxicity.
Adverse drug reactions reported in Study C2302 regardless of relationship to study medication are listed in Table 2. Adverse reactions considered at least possibly related to study medication are summarised in Table 2. Overall the most frequently reported adverse event was cough which was reported in 48% of the tobramycin capsules for inhalation dosage form group compared with 31% of the tobramycin solution group. Discontinuations due to cough were reported by 3.9% of the tobramycin capsules for inhalation dosage form group and 1.0% of the tobramycin solution group. Adverse drug reactions from Study C2302 are listed according to MedDRA system organ class in Table 2. Within each system organ class, the adverse reactions are ranked by frequency, with the most frequent reactions first, and by database. Within each frequency grouping, adverse 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 reaction.
Very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000), including isolated reports.
Bronchospasm was reported for 1.6% of the tobramycin capsules for inhalation dosage form group and 0.5% of the tobramycin solution group.
In Study C2302, hearing complaints such as tinnitus were reported in 1.9% of patients overall. Of the subsets of patients in this study who underwent serial audiology testing, 25.6% of the tobramycin capsules for inhalation dosage form group and 15.6% of the tobramycin solution group showed decreases from baseline at any visit; however, the majority of such changes were transient. Using the criteria of 10 dB loss at 3 consecutive frequencies, 15 dB loss at two consecutive frequencies and 20 dB loss at any one frequency for either ear, three tobramycin capsule patients and two tobramycin solution patients were judged to have ototoxicity. Deafness including deafness unilateral (reported as mild to moderate hearing loss or increased hearing loss) was reported in 1.0% of patients receiving tobramycin capsules for inhalation dosage form and 0.5% of patients receiving tobramycin solution. Aphonia was reported in 1.0% of the tobramycin capsules for inhalation dosage form group and 0% of the tobramycin solution group.
In the placebo-controlled Cycle 1 of Study C2301, which included 46 tobramycin capsules for inhalation dosage form patients and 49 placebo patients, ADRs included: pharyngolaryngeal pain (10.9% tobramycin capsules for inhalation dosage form vs. 0% placebo, very common) and dysphonia (4.3% tobramycin capsules for inhalation dosage form vs. 0% placebo, common) in the System Organ Class (SOC) Respiratory, Thoracic, and Mediastinal Disorders; and dysgeusia (6.5% tobramycin capsules for inhalation dosage form vs. 2.0% placebo, common) in the SOC Gastrointestinal Disorders.

Post-marketing surveillance.

Some patients receiving tobramycin solution and extensive previous or concomitant parenteral aminoglycosides have reported hearing loss during post-marketing surveillance (see Section 4.4 Special Warnings and Precautions for Use).
Adverse drug reactions derived from spontaneous reports for tobramycin solution. The following adverse drug reactions have been derived from post marketing experience with tobramycin solution via spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency which is therefore categorized as not known. Adverse drug reactions are listed according to system organ classes in MedDRA. Within each system organ class, ADRs are presented in order of decreasing seriousness.

Ear and labyrinth disorders.

Hearing loss.

Skin and subcutaneous tissue disorders.

Hypersensitivity, pruritus, urticaria, rash.

Nervous system disorders.

Aphonia, dysgeusia.

Respiratory, thoracic, and mediastinal disorders.

Bronchospasm, oropharyngeal pain, sputum increased, chest pain.

General disorders and administration site conditions.

Decreased appetite.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration 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 at www.tga.gov.au/reporting-problems.

4.9 Overdose

Signs and symptoms.

In the event of inadvertent administration of tobramycin by the IV route, signs and symptoms of parenteral toxicity from overdosage may occur that include dizziness, tinnitus, vertigo, loss of high-tone hearing acuity, respiratory distress or failure, renal impairment, and neuromuscular blockade. Administration by inhalation results in low systemic bioavailability of tobramycin.
In the event of accidental oral ingestion, systemic toxicity is unlikely as tobramycin is poorly absorbed from an intact gastrointestinal tract.
The maximum tolerated daily dose of tobramycin solution has not been established. Tobramycin serum concentrations may be helpful in monitoring overdose.

Treatment.

In all cases of suspected overdosage, physicians should contact the Poison Information Centre on 131 126 for advice on management. In the case of any overdosage, the possibility of drug interactions with alterations in drug disposition should be considered.
Acute toxicity should be treated with immediate withdrawal of tobramycin solution, and baseline tests of renal function should be undertaken.
Haemodialysis may be helpful in removing tobramycin from the body.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: 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. Tobramycin has in vitro activity against a wide range of gram-negative organisms including Pseudomonas aeruginosa (P. aeruginosa). It is bactericidal at concentrations equal to or slightly greater than inhibitory concentrations.

Susceptibility testing.

A single sputum sample from a cystic fibrosis (CF) patient may contain multiple morphotypes of P. aeruginosa and each morphotype may have a different level of in vitro susceptibility to tobramycin.
The in vitro antimicrobial susceptibility test methods used for parenteral tobramycin therapy can be used to monitor the susceptibility of P. aeruginosa isolated from CF patients. If decreased susceptibility is noted, the results should be reported to the clinician.
Susceptibility breakpoints established for parenteral administration of tobramycin do not apply to inhaled administration of tobramycin. The relationship between in vitro susceptibility test results and clinical outcome with tobramycin therapy is not clear.

Clinical trials.

Tobramycin capsules for inhalation are unavailable in this brand, however this dosage form is available in other brands. Clinical trial information obtained using the tobramycin capsules for inhalation formulation are also included for prescriber information.
Placebo-controlled studies.

Tobramycin solution.

Management of pulmonary Psuedomonas aeruginosa infection.

Two identically designed, double-blind, randomised, placebo-controlled, parallel group, 24-week clinical studies were conducted in 520 cystic fibrosis patients aged ≥ 6 years who had baseline FEV1% predicted between 25% and 75% and were positive for P. aeruginosa. Patients with a baseline creatinine of > 0.18 mmol/L or who had Burkholderia cepacia isolated from sputum were excluded. A cyclical treatment regimen consisting of 28 days on therapy followed by 28 days off therapy was used in these studies. This cycle was repeated twice for a total of three cycles. Patients received either tobramycin solution (300 mg) or placebo (saline with 1.25 mg quinine) twice daily, delivered by aerosol using a hand-held Pari LC Plus Reusable Nebuliser with a DeVilbiss Pulmo-Aide Compressor.
All patients received study drug in addition to standard treatment recommended for cystic fibrosis patients, which included oral and parenteral anti-pseudomonal therapy, β2-agonists, sodium cromoglycate, inhaled steroids, and airway clearance techniques. In addition, approximately 77% of patients were concurrently treated with dornase alfa.
The randomised clinical studies were followed by a 48-week open label extension where all patients who chose to continue received up to 6 cycles of treatment with tobramycin solution following the same regimen of 28 days on and 28 days off. Thus, patients who continued into the open label extension received a total exposure of either up to 9 cycles or up to 6 cycles, depending on their original assignment in the controlled studies.
In each of the two placebo-controlled studies, tobramycin solution-treated patients experienced significant improvement in pulmonary function. Improvement was demonstrated in the tobramycin solution group in Study 1 by an average increase in FEV1% predicted of about 11% relative to baseline (Week 0) during 24 weeks compared to no average change in placebo patients. In Study 2, tobramycin solution treated patients had an average increase of about 7% compared to an average decrease of about 1% in placebo patients. Figure 1 shows the average relative change in FEV1% predicted over 24 weeks for both studies.
Three hundred ninety-six (396) patients from the controlled studies participated in the open label extension. Of these, a total of 192 patients received up to 9 cycles of tobramycin solution, 3 cycles during the controlled studies and 6 cycles during the open label extension. At the end of cycle 9, in these patients FEV1% predicted was 1.7% above baseline (measured at the start of the controlled trials). A total of 204 patients received placebo for 3 cycles followed by 6 cycles of tobramycin solution. Whilst on placebo, these patients experienced a mean 2.9% decrease in FEV1% predicted from baseline. After 6 cycles of tobramycin solution, FEV1% predicted had improved to 1% below baseline (see Figure 2).
P. aeruginosa density in sputum was measured during the 24-week placebo-controlled studies. Treatment with tobramycin solution resulted in a significant reduction in the number of P. aeruginosa colony forming units (CFUs) in sputum during the on-drug periods. Sputum bacterial density returned to baseline during the off drug periods. Reductions in sputum bacterial density were smaller in each successive cycle (see Figure 3). P. aeruginosa density in sputum was not measured during the open label extension.
During the 24 weeks of the placebo-controlled studies, patients treated with tobramycin solution were hospitalised for an average of 5.1 days compared to 8.1 days for placebo patients. Patients treated with tobramycin solution required an average of 9.7 days of parenteral anti-pseudomonal antibiotic treatment compared to 14.1 days for placebo patients. During the 24 weeks of treatment, 40% of tobramycin solution patients and 53% of placebo patients were treated with parenteral antipseudomonal antibiotics. Over the subsequent 48 weeks of the open label extension, patients were hospitalised for a mean of 11.1 days. Patients were treated with parenteral antipseudomonal antibiotics for a mean of 22.4 days and 60.6% of patients were treated with parenteral antipseudomonal antibiotics.
The relationship between in vitro susceptibility test results and clinical outcome with tobramycin solution therapy is not clear. However, four tobramycin solution patients who began the clinical trial with P. aeruginosa isolates having MIC values ≥ 128 microgram/mL did not experience an improvement in FEV1 or a decrease in sputum bacterial density during the first 24 weeks of therapy.
For patients given 9 cycles of active treatment, the proportion of patients with isolates of P. aeruginosa with an MIC ≥ 16 microgram/mL increased from 13.7% at baseline to 29.8% at the end of cycle 9. The proportion of patients with isolates of P. aeruginosa with MIC ≥ 128 microgram/mL increased from 2.1% at baseline to 9.2% at the end of cycle 9.
During the open-label extension, susceptibility testing of other aminoglycosides (amikacin and gentamicin) indicated a shift toward increasing MIC values similar in magnitude to that seen for tobramycin. The MIC values for ciprofloxacin, aztreonam, ceftazidime and ticarcillin remained unchanged.
As noted in Figure 4, treatment for 18 months (9 cycles) with tobramycin solution in clinical studies demonstrated a trend to decreasing in vitro susceptibility of P. aeruginosa isolates. The clinical significance of changes in Minimum inhibitory concentrations (MICs) for P. aeruginosa has not been clearly established in the treatment of CF patients.

Tobramycin capsules for inhalation dosage form (study C2301).

Tobramycin capsules for inhalation dosage form was studied in a randomized, placebo-controlled, multicentre, three-cycle, two treatment group trial in CF patients, aged between 6 and 21 years (mean age 13.3 years), with FEV1 values from 25% to 80% (inclusive) predicted, who were infected with P. aeruginosa. Patients had no exposure to inhaled antipseudomonal antibiotics within 4 months prior to screening. The first cycle of this trial was conducted as a double-blind, randomized, placebo-controlled, parallel group trial. During the second and third cycles, all subjects were treated with tobramycin capsules for inhalation dosage form. Four capsules (112 mg tobramycin) were administered twice daily (each morning and evening), for three cycles of 28 days on-treatment and 28 days off-treatment (a total treatment period of 24 weeks).
Tobramycin capsules for inhalation dosage form significantly improved lung function compared with placebo, as shown by the results for the primary endpoint: relative increase in percent predicted FEV1 after 28 days of treatment (Table 3 and Figure 5). An analysis of covariance was employed for the efficacy analysis, with factors for treatment groups and regions and two continuous covariates (baseline FEV1% predicted and age). The sequential boundaries and stopping rules for the interim analysis were based on the Lan-DeMets procedure with an alpha-spending function that resembles the O'Brien-Fleming boundaries, to ensured control of the overall Type I error at the 0.5 level. A blinded review of the acceptability of spirometry data was conducted prior to study termination (recommended by an external Data Monitoring Committee) at the time of the interim analysis; all efficacy results below are derived from the sensitivity interim analysis after exclusion of technically unreliable spirometry data.
The improvements in lung function achieved during the first treatment cycle were maintained during the subsequent cycles of treatment with capsules. When patients in the placebo treatment group were switched from placebo to capsules at the start of the second treatment cycle, the relative change from baseline in percent predicted FEV1 was the same as that seen during the first treatment cycle in the tobramycin capsules for inhalation dosage form treatment group and the improvements were also maintained over time during the third treatment cycle.
The distribution of tobramycin MICs of P. aeruginosa isolates was characterized by biotype: mucoid, dry, small colony variants, and overall. Sputum assessments in this study showed that at baseline, 91% of tobramycin capsules for inhalation dosage form patients had P. aeruginosa isolates with an MIC at least 20 times lower than the mean sputum concentration observed within 30 minutes of dosing. At the end of the third 28 day dosing cycle, 86% of tobramycin capsules for inhalation dosage form patients had P. aeruginosa with an MIC at least 30 times lower and 89% of tobramycin capsules for inhalation dosage form patients had P. aeruginosa with a MIC at least 15 times lower than mean sputum concentration observed within 30 minutes of dosing. The sub-group of patients with MIC values > 8 microgram/mL at baseline had an improvement in FEV1% predicted measurements after 3 cycles of treatment when treated with tobramycin capsules for inhalation dosage form.
Active-controlled studies.

Tobramycin capsules for inhalation dosage form and tobramycin solution (study C2302).

Tobramycin capsules for inhalation dosage form and tobramycin solution were studied in a randomized, open-label, multicentre, three-cycle, parallel-arm trial in 553 CF patients, aged between 6 and 66 years (mean age 25.6 years), with FEV1 values from 25% to 75% (inclusive) predicted, who were infected with P. aeruginosa. Patients with no exposure to inhaled antipseudomonal antibiotics within 28 days prior to study drug administration were randomized in a 3:2 ratio to receive either tobramycin capsules for inhalation dosage form 112 mg (four 28 mg capsules) or tobramycin solution 300 mg (one 300 mg/5 mL ampoule). The study medications were administered twice daily, at the same time each morning and evening, approximately 12 hours (but not less than 6 hours) apart, for three cycles of 28 days on-treatment and 28 days off-treatment (a total treatment period of 24 weeks). Blinding was not possible due to differences in study drug administration. Baseline demographics, disease characteristics and use of concomitant medications were similar between the two treatment groups.
The primary objective of the study was to assess the safety of tobramycin capsules for inhalation dosage form compared to tobramycin solution. The main secondary objective was to assess the efficacy of tobramycin capsules for inhalation dosage form compared to tobramycin solution, the key efficacy variable was the relative change in FEV1 percent predicted at the end of Cycle 3 compared to baseline. A formal analysis of non-inferiority of tobramycin capsules for inhalation dosage form relative to tobramycin solution was conducted based on a one-sided 85% confidence interval calculated from an analysis of covariance (ANCOVA) of relative change in FEV1% predicted from baseline to pre-dose Day 28 of Cycle 3. The non-inferiority margin of delta = 6% was pre-defined. Treatment with both tobramycin capsules for inhalation dosage form and tobramycin solution 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 (Figure 6).
In Study C2302, at the end of the third active treatment period, there was a greater decrease in the mean change from baseline in log10 CFUs in both the tobramycin capsules for inhalation dosage form treatment group (-1.61 log10 CFUs) and tobramycin solution treatment group (-0.77 log10 CFUs) especially during the third treatment cycle (a mean change of -1.61 log10 CFUs in the capsules for inhalation dosage form treatment group compared with -0.77 log10 CFUs in the tobramycin solution treatment group. As in the previous study, there was a partial recovery of P. aeruginosa density at the end of the 28 day off-treatment phase in both treatment groups, but this was reversed during the on-treatment phase of each treatment cycle.
The mean time to administer a nebulised dose of tobramycin solution was approximately 20 minutes, compared with 6 minutes to administer a dose of tobramycin capsules for inhalation dosage form through the dry powder inhaler. This time excludes any set up and breakdown time for the nebuliser used with tobramycin solution.
In Study C2302, patients' satisfaction with treatment was assessed using a modified Treatment Satisfaction Questionnaire for Medication (TSQM) as part of the secondary objective. Patients consistently reported higher levels of satisfaction with treatment with tobramycin capsules for inhalation dosage form compared with tobramycin solution, particularly for assessments of effectiveness, convenience and overall satisfaction.
In study C2302, the proportions of patients in the tobramycin capsules for inhalation dosage form and tobramycin solution treatment groups requiring hospitalization for respiratory events was 24.4% and 22.0% respectively. The duration of hospitalizations was 15.6 days and 15.3 days respectively.

5.2 Pharmacokinetic Properties

Absorption.

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

Sputum concentrations.

Ten minutes after inhalation of the first 300 mg dose, the average concentration of tobramycin was 1237 microgram/g (ranging from 35 to 7414 microgram/g) in sputum. Tobramycin does not accumulate in sputum; after 20 weeks of therapy with the tobramycin solution regimen, the average concentration of tobramycin at ten minutes after inhalation was 1154 microm/g (ranging from 39 to 8085 microm/g) in sputum. High variability of tobramycin concentration in sputum was observed. Two hours after inhalation, sputum concentrations declined to approximately 14% of tobramycin levels at ten minutes after inhalation.

Serum concentrations.

The average serum concentration of tobramycin one hour after inhalation of a single 300 mg dose of tobramycin solution by CF patients was 0.95 microgram/mL. After 20 weeks of therapy on the tobramycin solution regimen, the average serum tobramycin concentration one hour after dosing was 1.05 microgram/mL.

Distribution.

A population pharmacokinetic analysis for tobramycin using the capsules for inhalation dosage form in CF patients estimated the apparent volume of distribution of tobramycin in the central compartment to be 84.1 L for a typical CF patient. While the volume was shown to vary with body mass index (BMI) and lung function (as FEV1% predicted), model-based simulations showed that peak (Cmax) and trough (Ctrough) concentrations were not impacted markedly with changes in BMI or lung function. Binding of tobramycin to serum proteins is negligible.

Metabolism.

Tobramycin is not metabolized and is primarily excreted unchanged in the urine.

Excretion.

The elimination half-life of tobramycin from serum is approximately 2 hours after intravenous (IV) administration. The apparent terminal half-life of tobramycin in serum after inhalation of a single 300 mg dose of tobramycin solution was approximately 3 hours in CF patients in both dosage forms. Assuming tobramycin absorbed following inhalation behaves similarly to tobramycin following IV administration; systemically absorbed tobramycin is eliminated principally by glomerular filtration. Unabsorbed tobramycin, following tobramycin solution administration, is probably eliminated primarily in expectorated sputum.

Effect of food.

Assessments of food-effect were not performed as tobramycin solution is administered by inhalation.

Characteristics in special populations.

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 153 mmol/L or more and blood urea nitrogen (BUN) 14 mmol/L 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 tobramycin solution. See Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration.

Hepatic impairment.

No studies have been performed on patients with hepatic impairment. As tobramycin is not metabolized, 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 tobramycin solution in these patients.

Elderly patients.

Renal function in elderly patients should be taken into account as systemically absorbed tobramycin is primarily excreted unchanged in the urine. See Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration.

Paediatric population below 6 years.

No pharmacokinetic studies have been conducted in children below 6 years of age. Children 6 years and older have been included in clinical studies in which there was no dose adjustment made based on age or weight.

Race.

Ethnic sensitivity studies have not been conducted. Since tobramycin is not metabolized, it is not expected that ethnic origin would influence exposure.

5.3 Preclinical Safety Data

Animal toxicology.

Bronchoepithelial hyperplasia and chronic interstitial inflammation around terminal bronchioles occurred in studies in rats after daily inhalational exposures to tobramycin for 6 months.

Genotoxicity.

Tobramycin has been evaluated for genotoxicity in a battery of assays for gene mutations and chromosomal damage. Tobramycin was negative in the bacterial reverse mutation and the mouse lymphoma forward mutation assays. Tobramycin did not induce chromosomal aberrations in Chinese hamster ovary cells and was negative in the mouse micronucleus test.

Carcinogenicity.

A two-year rat inhalation toxicology study to assess the carcinogenic potential of tobramycin has been completed. Rats were exposed to tobramycin for up to 1.5 h/day for 95 weeks. Serum levels of tobramycin of up to 35 microgram/mL were measured in rats, in contrast to the maximum 1.99 ± 0.59 microgram/mL level observed in CF patients in clinical trials. At the highest doses in rats, the estimated dose of tobramycin deposited in the lungs and adjusted for body surface area, was similar to the human clinical dose. There was no drug-related increase in the incidence of any variety of tumour.

6 Pharmaceutical Particulars

6.1 List of Excipients

See Section 2 Qualitative and Quantitative Composition.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Tobramycin solution should be stored under refrigeration at 2°C-8°C. Do not freeze. Upon removal from the refrigerator, or if refrigeration is unavailable, tobramycin pouches (opened or unopened) may be stored at room temperature (up to 25°C) for up to 28 days.
Tobramycin WKT solution should not be used beyond the expiration date stamped on the ampoule when stored under refrigeration (2°C-8°C) or beyond 6 months when stored at room temperature (up to 25°C). Tobramycin WKT solution should not be used if it is cloudy or if there are particles in the solution.
Tobramycin WKT solution ampoules should not be exposed to intense light. The solution in the ampoule is slightly yellow, but may darken with age if not stored in the refrigerator; however, the colour change does not indicate any change in the quality of the product as long as it is stored within the recommended storage conditions.
The contents of the whole ampoule should be used directly after opening; opened ampoules should never be stored for re-use.

6.5 Nature and Contents of Container

Tobramycin WKT solution for inhalation is supplied in single-use, low-density polyethylene plastic 5 mL ampoules, containing 300 mg tobramycin. Tobramycin WKT solution is packaged in laminated foil over-pouches, each containing 7 ampoules. AUST R 279353.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.


Chemical formula: C18H37N5O9.
Chemical name: O-3-amino-3-deoxy-α-D-glucopyranosyl-(1→4)-O-[2,6-diamino- 2,3,6-trideoxy-α-D-ribo-hexopyranosyl-(1 → 6)]-2-deoxy-L- streptamine.
Molecular weight: 467.52.
Tobramycin is a white or almost white hygroscopic powder. It is freely soluble in water, very slightly soluble in alcohol and practically insoluble in chloroform and in ether. The dissociation constant pKa's are pKa1 5.8; pKa2 6.8; pKa3 7.1; pKa4 7.9; pKa5 9.3. The partition coefficient is Log P-4.224 + 0.848.

CAS number.

32986-56-4.

7 Medicine Schedule (Poisons Standard)

Schedule 4.

Summary Table of Changes