Consumer medicine information

Tobramycin Wockhardt

Tobramycin

BRAND INFORMATION

Brand name

Tobramycin Wockhardt

Active ingredient

Tobramycin

Schedule

What is in this leaflet

This leaflet answers some common questions about TOBRAMYCIN WOCKHARDT

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the final page. More recent information on the medicine may be available.

You should ensure that you speak to your pharmacist or doctor to obtain the most up to date information on the medicine.

All medicines have benefits and risks. Your doctor has weighed the risks of using TOBRAMYCIN WOCKHARDT against the benefits it is expected to have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine. You may need to read it again.

What TOBRAMYCIN WOCKHARDT is used for

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

Tobramycin belongs to a class of antibiotics called aminoglycosides. It works by killing or stopping the growth of the bacteria that cause the 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.

Some people do not get this infection until later on in their lives, while others get very young. If the infection is not properly fought, it will continue to damage your lungs, causing further problems with your breathing. TOBRAMYCIN WOCKHARDT solution has been specially formulated for administration by inhalation via a nebuliser and compressor. When you inhale TOBRAMYCIN WOCKHARDT the antibiotic can get straight into your lungs to fight against the infection and to improve your breathing.

For best results, please use TOBRAMYCIN WOCKHARDT as this leaflet instructs you.

Although TOBRAMYCIN WOCKHARDT does not cure your condition, it does help control it. TOBRAMYCIN WOCKHARDT is not recommended for use in children younger than 6 years of age, as there have been no studies of its effects in this age group.

Ask your doctor if you have any questions about why this medicine has been prescribed for you. Your doctor may have prescribed TOBRAMYCIN WOCKHARDT for another reason.

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

Before you use TOBRAMYCIN WOCKHARDT

When you must not use it

Do not use TOBRAMYCIN WOCKHARDT if you have an allergy to:

TOBRAMYCIN WOCKHARDT or any other tobramycin medicine, e.g. Nebcin®
any antibiotics that belong to the aminoglycoside group (e.g. amikacin, gentamicin, neomycin, or streptomycin)
any of the other ingredients listed at the end of this leaflet.

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.

If you think that you may be allergic, ask your doctor for advice.

Do not use TOBRAMYCIN WOCKHARDT

after the expiry date printed on the pack has passed
if the packaging is torn or shows signs of tampering.

In that case, return it to your pharmacist. If you use this medicine after the expiry date has passed, it may not work as well.

Do not give TOBRAMYCIN WOCKHARDT to a child below the age of 6, unless directed to by the child's doctor or pharmacist. TOBRAMYCIN WOCKHARDT is not recommended for use in children under 6 years.

If you are not sure whether you or your child should start using TOBRAMYCIN WOCKHARDT talk to your doctor or pharmacist. If you are not sure whether you should use this medicine, talk to your doctor.

Before you start to use it

Tell your doctor if you are pregnant or intend to become pregnant. TOBRAMYCIN WOCKHARDT 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 WOCKHARDT during pregnancy.

Tell your doctor if you are breast feeding or plan to breast-feed. 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 WOCKHARDT during breast-feeding.

Tell your doctor if you have or have had any medical conditions, especially the following:

kidney problems
hearing problems, including noises in the ears and dizziness
unusual difficulty in breathing with wheezing or coughing, chest tightness
trouble with your balance
dizzy spells
problems with nerve or muscle function
muscle weakness that lasts, or becomes worse in time, a symptom mostly related to conditions such as Parkinson's disease (a condition of the brain affecting movement) or myasthenia (a condition in which the muscles become weak and tire easily).

Tell your doctor if you have allergies to any other medicines or any other substances, such as foods, preservatives or dyes. Your doctor will want to know if you are prone to allergies.

If you are aged 65 years or older, your doctor may perform additional tests to decide if TOBRAMYCIN WOCKHARDT is right for you.

If you have not told your doctor about any of the above, tell them before you start using TOBRAMYCIN WOCKHARDT.

Taking other medicines

Tell your doctor if you are using or have recently taken any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and TOBRAMYCIN WOCKHARDT 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).

These medicines may be affected by TOBRAMYCIN WOCKHARDT or may affect how well it works. You may need different amounts of your medicine, or you may need to take different medicines.

Your doctor or pharmacist will advise you.

Your doctor and pharmacist may have more information on medicines to be careful with or avoid while using TOBRAMYCIN WOCKHARDT.

How to use TOBRAMYCIN WOCKHARDT

How much to use

Inhale TOBRAMYCIN WOCKHARDT only when prescribed by your doctor.

Do not exceed the recommended dose. The recommended dose of TOBRAMYCIN WOCKHARDT 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 WOCKHARDT.

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.

How to use it

TOBRAMYCIN WOCKHARDT 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 WOCKHARDT therapy.

Breathe normally through the mouthpiece of the nebuliser until all of the TOBRAMYCIN WOCKHARDT 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 it

Please check the order of medications with your doctor. If you are taking several different inhaled treatments and performing therapies for cystic fibrosis, you should use TOBRAMYCIN WOCKHARDT LAST.

Use TOBRAMYCIN WOCKHARDT 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 WOCKHARDT 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 WOCKHARDT

Wash your hands thoroughly with soap and water and fully dry hands.
Just before use, cut or tear open the foil pouch and remove one TOBRAMYCIN WOCKHARDT ampoule by gently pulling apart one of the attached ampoules at the bottom tabs.
Put the other ampoule(s) back in the foil pouch and keep it in the refrigerator.
Lay out 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
Check that you have the suitable compressor, and tubing to connect the nebuliser and compressor.
Follow the appropriate instructions for use for your type of nebuliser. You must read the leaflet provided with the nebuliser by the manufacturer.
Check that your nebuliser and compressor are working properly according to the manufacturer's instructions before you start to take your medicine.
Remove the nebuliser top from the nebuliser cup by twisting the top anticlockwise and then lifting it.
Place the nebuliser top on the towel and stand the nebuliser cup upright on the towel.
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.
Open the TOBRAMYCIN WOCKHARDT ampoule by holding the bottom tab with one hand and twisting off the top with your other hand.
Squeeze all the contents of the ampoule into the nebuliser cup.
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.
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.
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 use a nose clip if your doctor agrees). Try not to block the airflow with your tongue.
Continue until all of the TOBRAMYCIN WOCKHARDT. 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.

How long to use it

Use TOBRAMYCIN WOCKHARDT twice daily every day for 28 days, followed by a 28 day period off TOBRAMYCIN WOCKHARDT.

Continue using TOBRAMYCIN WOCKHARDT in these 28 day on/28 day off cycles for as long as your doctor or pharmacist tells you.

If you have any questions about how long to use TOBRAMYCIN WOCKHARDT ask your doctor or pharmacist.

If you forget to use it

If there are at least 6 hours to your next dose, use TOBRAMYCIN WOCKHARDT 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 have your next TOBRAMYCIN WOCKHARDT dose when you are meant to.

Do not have a double dose to make up for the dose that you missed. This may increase the chance of you getting an unwanted side effect.

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

If you have trouble remembering to use your medicine, ask your pharmacist for some hints.

If you use too much (overdose)

Immediately telephone your doctor, or Poisons Information Centre (telephone Australia 131126 or New Zealand 0800 POISON or 0800 764 766) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have used too much Tobramycin Wockhardt.

Do this even if there are no signs of discomfort or poisoning.

Signs of an overdose may include:

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

While you are using TOBRAMYCIN WOCKHARDT

Things you must do

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

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

If you are interrupted, or need to cough or rest during your TOBRAMYCIN WOCKHARDT 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 WOCKHARDT tell your doctor immediately.

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

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

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

Things you must 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 WOCKHARDT which you have stored at room temperature for more than 28 days. Do not dilute or mix other medications, with TOBRAMYCIN WOCKHARDT in the nebuliser.

Never use a dirty or clogged nebuliser.

Do not share your nebuliser with other people.

Do not give TOBRAMYCIN WOCKHARDT to anyone else, even if they have the same condition as you.

Do not use TOBRAMYCIN WOCKHARDT to treat any other complaints unless your doctor tells you to.

Do not stop using TOBRAMYCIN WOCKHARDT 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 WOCKHARDT 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.

Be careful driving or operating machinery until you know how TOBRAMYCIN WOCKHARDT affects you. TOBRAMYCIN WOCKHARDT may cause dizziness, ringing in the ears, or light-headedness in some people. If you drink alcohol, dizziness or light-headedness may be worse.

If you feel dizzy or light-headed after using TOBRAMYCIN WOCKHARDT do not drive. Make sure you know how you react to TOBRAMYCIN WOCKHARDT before you drive a car, operate machinery, use tools, or do anything else that could be dangerous if you are dizzy or light-headed.

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.

SIDE EFFECTS

TOBRAMYCIN WOCKHARDT helps most people with cystic fibrosis, but can cause side effects in a few people.

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using TOBRAMYCIN WOCKHARDT.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have. Tell your doctor If you notice any of the following and that worry you:

runny or stuffy nose
sneezing
voice alteration with or without a sore throat
difficulty swallowing (laryngitis)
discolouration of the substance you cough up (sputum)
decreased results for the tests of lung function
muscle pain
generally feeling unwell
itching or itchy rash
loss of your voice
sore throat
disturbed sense of taste.

Tell your doctor immediately if you notice any of the following:

ringing in the ears
hearing loss
noises in the ears (such as hissing)
dizziness
light-headedness
clumsiness and 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).

These may be serious side effects of TOBRAMYCIN WOCKHARDT. You may need urgent medical attention. Serious side effects are rare.

Tell your doctor immediately or go to accident and emergency at your nearest hospital if you notice any of the following:

swelling of the face, lips, mouth, throat or tongue which may cause difficulty in swallowing or breathing
shortness of breath
skin rash
unusual difficulty in breathing, with wheezing or coughing or chest tightness
worsening of your underlying lung Disease.

These are serious side effects. If you have them, you may have had a serious allergic reaction to TOBRAMYCIN WOCKHARDT.

You may need urgent medical attention or hospitalisation.

Tell your doctor if you notice anything that is making you feel unwell.

Other side effects not listed may occur in some patients.

After using TOBRAMYCIN WOCKHARDT

Cleaning

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.

Storage

Store TOBRAMYCIN WOCKHARDT between 2-8°C in the refrigerator. If you do not have a refrigerator available (for example, when you are transporting TOBRAMYCIN WOCKHARDT), 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 WOCKHARDT Once opened, the solution should be used immediately.

Do not leave this medicine in the car on hot days or on window sills. Heat and intense light can destroy some medicines.

Keep TOBRAMYCIN WOCKHARDT where children cannot reach it. A locked cupboard at least one and a half meters above the ground is a good place to store medicines.

Disposal

If your doctor tells you to stop using TOBRAMYCIN WOCKHARDT or the solution has passed its expiry date, ask your pharmacist what to do with any that is leftover. Medicines should not be disposed of in household waste. These measures will help to protect the environment.

Product description

What it looks like

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

TOBRAMYCIN WOCKHARDT is supplied in clear, single-use low density polyethylene ampoule that is packaged in foil pouches.

Ingredients

Active ingredient:

Each 5 mL single dose ampoule contains tobramycin 300 mg.

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.

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

Sponsor

Wockhardt Bio Pty Ltd
Suite 103, 39 East Esplanade,
MANLY NSW 2095
Australia

Australian Registration Numbers

279354

Date of preparation

This leaflet was prepared in Mar 2018

Published by MIMS March 2019

BRAND INFORMATION

Brand name

Tobramycin Wockhardt

Active ingredient

Tobramycin

Schedule

1 Name of Medicine

Tobramycin.

2 Qualitative and Quantitative Composition

Tobramycin Wockhardt solution for inhalation is a formulation of tobramycin specifically developed for administration by inhalation.
Tobramycin Wockhardt 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 Wockhardt 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.
Tobramycin is a white or almost white hygroscopic powder.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Sterile solution for inhalation in ampoules.

4 Clinical Particulars

4.1 Therapeutic Indications

Tobramycin Wockhardt 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 FEV ≤ 25% or ≥ 80% predicted at screening, or patients colonized with Burkholderia cepacia (see Section 5.1 Pharmacodynamic Properties).

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 Wockhardt 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 have not been studied and are 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 Wockhardt 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.

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 Clostridium 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 Clostridium 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 elderly.

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

Paediatric use.

The safety and efficacy of tobramycin have 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, cyclosporin, 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 domase 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)

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.

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).
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. 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.

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 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 Poison 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.

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 anti-pseudomonal 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 anti-pseudomonal antibiotics for a mean of 22.4 days and 60.6% of patients were treated with parenteral anti-pseudomonal 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 anti-pseudomonal 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 anti-pseudomonal 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 Δ = 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 capsule 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 micrometer/g (ranging from 39 to 8085 micrometer/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 (C_max) and trough (C_trough) 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. 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 Wockhardt 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 Wockhardt solution should not be used if it is cloudy or if there are particles in the solution.
Tobramycin Wockhardt 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 Wockhardt solution for inhalation is supplied in single-use, low-density polyethylene plastic 5 mL ampoules, containing 300 mg tobramycin. Tobramycin Wockhardt solution is packaged in laminated foil over-pouches, each containing 7 ampoules. AUST R 279354.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

6.7 Physicochemical Properties

Chemical formula: C₁₈H₃₇N₅O₉.

Chemical structure.

CAS number.

32986-56-4.
Chemical name: O-3-amino-3-deoxy-α-D-glucopyranosyl-(l→4)-O- [2,6-diamino- 2,3,6-trideoxy-α-D-ribo-hexopyranosyl-(l→6)]-2-deoxy-L- streptamine.
Molecular weight: 467.52.
Tobramycin 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.

7 Medicine Schedule (Poisons Standard)

S4.

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Consumer medicine information

Tobramycin Wockhardt

Tobramycin

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