Consumer medicine information

TOBRA-DAY

Tobramycin

BRAND INFORMATION

Brand name

Tobra-Day

Active ingredient

Tobramycin

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using TOBRA-DAY.

SUMMARY CMI

Tobra-day® Injection

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 is Tobra-day being given?

Tobra-day contains the active ingredient tobramycin sulfate. Tobra-day is an antibiotic given to treat serious lung infections caused by bacteria in patients with cystic fibrosis. It works by killing the bacteria causing the infection.

For more information, see Section 1. Why is Tobra-day being given? in the full CMI.

2. What should I know before Tobra-day is given?

Do not use if you have ever had an allergic reaction to Tobra-day 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 Tobra-day is given? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with Tobra-day 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 is Tobra-day given?

Tobra-day is always given to you under the supervision of your doctor or healthcare professional. Your doctor will decide what dose and how long you will receive it for.

More instructions can be found in Section 4. How is Tobra-day given? in the full CMI.

5. What should I know while Tobra-day is being given?

Things you should do
  • If you are about to be started on any new medicine, remind your doctor and pharmacist that you have been given Tobra-day.
  • Remind any doctor, dentist, pharmacist or nurse you visit that you have been given Tobra-day.
  • If you become pregnant while being given Tobra-day, tell your doctor immediately.
  • If you are going to have surgery, tell the surgeon or anaesthetist that you have been given this medicine.
  • Keep all your doctor's appointments so that your progress can be checked.
Driving or using machines
  • Be careful driving or operating machinery after you have been given Tobra-day.
Looking after your medicine
  • Tobra-day will be stored in the surgery, pharmacy or ward of a hospital, refrigerated between 2°C and 8°C but not frozen.

For more information, see Section 5. What should I know while Tobra-day is being given? in the full CMI.

6. Are there any side effects?

Tobra-day may cause headache, fever, chills, nausea, vomiting, loss of appetite and weakness, redness and swelling at the site of the injection, burning or creeping sensation of the skin, kidney problems, hearing loss, dizziness and vertigo, shortness of breath, wheezing or difficulty breathing, swelling of the face, lips, tongue or other parts of the body, rash, itching or hives on the skin.

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

Tobra-day® Injection (toe-bruh-my-sin)

Active ingredient: tobramycin sulfate

Consumer Medicine Information (CMI)

This leaflet provides important information about using Tobra-day. You should also speak to your doctor or pharmacist if you would like further information or if you have any concerns or questions about Tobra-day Injection being given.

Where to find information in this leaflet:

1. Why is Tobra-day being given?
2. What should I know before Tobra-day is given?
3. What if I am taking other medicines?
4. How is Tobra-day given?
5. What should I know while Tobra-day is being given?
6. Are there any side effects?
7. Product details

1. Why is Tobra-day being given?

Tobra-day contains the active ingredient tobramycin sulfate. Tobra-day belongs to a group of medicines called aminoglycosides.

Tobra-day is an antibiotic used to treat serious lung infections caused by bacteria in patients with cystic fibrosis. It works by killing the bacteria causing the infection.

Follow all directions given to you by your doctor, nurse or pharmacist. They may differ from the information contained in this leaflet.

If you do not understand any instructions given to you by your doctor, nurse or pharmacist ask them for help.

Your doctor may have prescribed it for another reason.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

2. What should I know before Tobra-day is given?

Warnings

Tobra-day should not be given to children under 5 years of age. There is not enough information to recommend the use of this medicine for children under the age of 5 years.

You should not be given Tobra-day if:

  • you or your family members have a mitochondrial mutation disease (condition caused by variants in the genome of mitochondria, the parts of your cell which help make energy) or of loss of hearing due to antibiotic medicines; certain mitochondrial mutations may increase your risk of hearing loss with this product.
  • you have had hearing loss or severe dizziness after being treated with tobramycin or other aminoglycosides.
  • the solution is discoloured, cloudy, turbid, or a precipitate is present. The injection is normally a clear colourless solution. The solution is normally a clear straw coloured liquid.
  • it causes a precipitate, discolouration or cloudiness to form when added to an intravenous (IV) solution.
  • the date is after the expiry date printed on the pack, or if the packaging is torn or shows signs of tampering. The doctor or nurse will check to ensure the medicine is not past the expiry date and has not been tampered with.
  • you are allergic to
    - any medicine containing tobramycin or tobramycin sulfate, or any of the ingredients listed at the end of this leaflet.
    - any other aminoglycoside antibiotic such as streptomycin, gentamicin, amikacin, kanamycin, netilmicin or neomycin.

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

Check with your doctor if you:

  • have allergies to any medicines, food, preservatives, or dyes.
  • have or have had the following medical conditions:
    - a history of kidney problems including if these develop while being given Tobra-day
    - hearing loss
    - dizziness, spinning sensation or ringing in the ears
    - previous hearing loss or dizziness while being given Tobra-day
    - Parkinson's disease
    - conditions causing muscle weakness such as myasthenia gravis.
  • or your family members have a mitochondrial mutation disease (condition caused by variants in the genome of mitochondria, the parts of your cell which help make energy) or of loss of hearing due to antibiotic medicines; certain mitochondrial mutations may increase your risk of hearing loss with this product.

If you are not sure whether you should be given Tobra-day talk to your doctor.

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.

Talk to your doctor if you are breastfeeding or intend to breastfeed. Tobra-day passes into the breast milk and there is a possibility that the baby may be affected.

If you have not told your doctor about any of the above, tell them before you are given Tobra-day.

3. What if I am taking other medicines?

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

Some medicines may interfere with Tobra-day and affect how it works. These include but are not limited to:

  • penicillin or other penicillin type antibiotics or cephalosporin
  • medicines used to relax muscles
  • pain killers
  • cough and cold remedies
  • alcohol
  • heart or blood pressure medications.

You must not be given Tobra-day if you are taking:

  • diuretics or fluid tablets such as frusemide or ethancynic acid
  • antibiotics such as polymyxin B, colistin, cisplatin, vancomycin
  • aminoglycoside antibiotics such as neomycin, streptomycin, gentamycin, amikacin, kanamycin or netilmicin
  • antibiotics used to treat fungal infections such as amphotericin B
  • ibuprofen, a medicine used to treat pain, fever and arthritis
  • methoxyflurane a medicine used to reduce pain during medical procedures.

These medicines may be affected by Tobra-day or may affect how well Tobra-day works. You may need different amounts of your medicines, or you may need to take difference medicines.

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

4. How is Tobra-day given?

Tobra-day must only be given by a doctor or a healthcare professional.

How it is given

Tobra-day is used in a certain dose as a once a day injection. This once a day injection works just as well as giving a number of smaller doses throughout a day.

It should be diluted in a suitable solution and slowly infused into a vein over a period of 30 to 60 minutes.

How much is given

  • Your doctor will decide what dose of Tobra-day you will receive and how long you will receive it for. This depends on your medical condition and other factors such as your weight.
  • Tobra-day is given as a slow injection once a day.

If you are given too much Tobra-day

Overdose is unlikely to occur as Tobra-day is always given to you under the supervision of a doctor.

However, if you notice any symptoms of an overdose even weeks after being given Tobra-day, 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. You may need urgent medical attention.

Symptoms of an overdose may include:

  • drowsiness
  • hearing loss
  • dizziness, spinning sensation or ringing in the ear
  • passing little or no urine
  • difficulty breathing, breathlessness.

5. What should I know while Tobra-day is being given?

Things you should do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you have been given Tobra-day.

Tell any other doctors, dentists, and pharmacists who treat you that you have been given Tobra-day.

If you are going to have surgery, tell the surgeon or anesthetist that you have been given this medicine.

Keep all your doctor's appointments so that your progress can be checked. Your doctor may do some tests from time to time to make sure this medicine is working and to prevent unwanted side effects.

Call your doctor straight away if you:

  • become pregnant while being given Tobra-day.

Remind any doctor, dentist, pharmacist, or nurse you visit that you have been given Tobra-day.

If you feel light-headed, dizzy, or faint when getting out of bed or standing up, get up slowly.

Standing up slowly, especially when you get up from a bed or a chair, will help your body get used to the change in position and blood pressure. If this problem continues to get worse talk to your doctor.

Driving or using machines

Be careful driving or operating machinery after you have been given Tobra-day.

Tobra-day may cause dizziness or tiredness in some people. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Looking after your medicine

Tobra-day will

  • be stored in the surgery, pharmacy, or ward of a hospital, refrigerated between 2°C and 8°C but not frozen.
  • only be opened when it is time for you to have the injection.

It will be kept where young children cannot reach it.

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.

The risk of side effects increases if you

  • have poor kidney function
  • are elderly
  • are on a long-term medical treatment
  • have a serious medical condition.

Do not be alarmed by the following list of side effects. You may not experience any of them.

Less serious side effects

Less serious side effectsWhat to do
  • nausea, vomiting, diarrhoea
  • nausea, loss of appetite and weakness
  • mild rash, itching
  • tiredness, muscle weakness
  • disorientation
  • numbness or weakness of arms and legs
  • headache, fever, chills
  • unusual bruising or bleeding under the skin
  • sore mouth, throat or mouth ulcer
  • looking pale, lack of energy
  • burning or creeping sensation of the skin
  • redness and swelling at the injection site
  • yellowing of the skin and eyes
  • swollen painful abdomen
Speak to your doctor if you have any of these less serious side effects and they worry you.
This list includes the more common side effects of your medicine.

Serious side effects

Serious side effectsWhat to do
  • kidney problems, e.g. increase or decrease in urination
  • ringing in the ears (known as tinnitus)
  • hearing loss
  • dizziness and vertigo
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.

Very serious side effects

Very serious side effectsWhat to do
  • swelling of the face, lips, tongue or other parts of the body may be experienced.
  • rash, itching or hives on the skin
  • shortness of breath, wheezing or difficulty breathing
These may be symptoms of an allergic reaction to tobramycin.		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.
These side effects are very rare.

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 affects 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

Tobra-day is a prescription medicine and is only administered under a doctor's supervision.

What Tobra-day contains

Active ingredient
(main ingredient)		Tobramycin sulfate equivalent to 500 mg of tobramycin
Other ingredients
(inactive ingredients)		Sulfuric acid
Sodium hydroxide
Water for injections

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

Tobra-day does not contain lactose, sucrose, gluten, tartrazine, alcohol, dyes or any preservatives.

What Tobra-day looks like

Tobra-day is a clear straw coloured solution in an amber glass vial with a rubber stopper and aluminum seal with plastic flip off cap.

It is supplied in a 7 mL vial with 5 mL of solution in packs of 10.

(AUST R 150481)

Who distributes Tobra-day

Tobra-day is made in Australia by:

Phebra Pty Ltd
19 Orion Road, Lane Cove West,
NSW 2066, Australia.
Telephone: 1800 720 020.

Tobra-day is distributed in New Zealand by:

AFT Pharmaceuticals Ltd
PO Box 33-203 Takapuna,
Auckland, New Zealand.

This leaflet was prepared in July 2022.

Tobra-day, Phebra and the Phi symbol are trademarks of Phebra Pty Ltd, 19 Orion Road, Lane Cove West, NSW 2066, Australia.

Published by MIMS September 2022

BRAND INFORMATION

Brand name

Tobra-Day

Active ingredient

Tobramycin

Schedule

S4

 

1 Name of Medicine

Tobramycin sulfate.

2 Qualitative and Quantitative Composition

Each mL of Tobra-Day concentrated injection for intravenous infusion contains 100 mg tobramycin. The solution is preservative free. The pH of Tobra-Day is between 3.5 and 6.0.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Concentrated injection for intravenous infusion. Tobra-Day is a clear, straw coloured solution.

4 Clinical Particulars

4.1 Therapeutic Indications

Tobra-Day is indicated for once daily intravenous use in the treatment of cystic fibrosis (CF) patients (> 5 years old) with acute pulmonary exacerbations caused by susceptible organisms.

4.2 Dose and Method of Administration

In patients with cystic fibrosis, the starting dose is 10 mg tobramycin per kg bodyweight per day. The dose is adjusted according to the results of therapeutic drug monitoring (TDM).
Initial dose selection (10 mg/kg/day) should be adjusted depending on renal function and previous patient experience. Further dose adjustment should take into account the results of therapeutic drug monitoring, renal function and audiometry testing.
The intravenous injection is diluted in a minimum volume of 50 mL of sodium chloride intravenous infusion (0.9% w/v) or 5% glucose intravenous infusion and infused over thirty to sixty minutes.
Once diluted the solution should be used as soon as possible. If storage is necessary the prepared solution should be refrigerated between 2°C and 8°C and stored for no longer than 24 hours before discarding.

Monitoring serum levels of tobramycin.

Monitoring of tobramycin plasma levels may be carried out by a number of methods using various nonograms and computer programs which use the area under curve method (Barclay et al)1. Traditional methods of monitoring for tobramycin toxicity using peak and trough levels are ineffective when giving tobramycin once a day (Coulthard et al)2. This is because higher peak levels will be achieved and trough levels are often unrecordable. The aim of TDM is to achieve adequate bactericidal effect with minimum toxicity as these patients will usually receive tobramycin for between 10 to 14 days, and in some cases longer.
The recommended method to achieve precise dosing and aid with dose adjustment is the use of a computer program for therapeutic drug monitoring accessed by a pharmacist (Duffull et al)3.
Blood levels should be taken one hour and four to six hours post the first dose. Also required is the patient's height, weight, age and serum creatinine. The dose, time of administration and the time blood levels were taken are also required for the calculation.
The following target levels can be used as a guide only:
Cmax: > 20 mg/L; Cmin: < 0.5 mg/L; AUC: 85-101 mg.h/L.
If the dose is altered by more than 40 mg, blood levels should be repeated as above. If there is no alteration in dose, blood levels should be taken at least weekly for the duration of treatment.

Other monitoring recommendations to prevent toxicity.

Regular serum creatinine levels to assess for renal toxicity at least weekly but more frequently if the patient is clinically unstable.
Ototoxicity should be monitored using audiometry preferably at the end of each admission.
Tobra-Day contains no antimicrobial agent and is for single use in one patient on one occasion only. Discard any residue.
Tobra-Day and other antibiotics should be administered separately.

Further information.

Further information concerning use of tobramycin in once-a-day regimens may be found in the Australian Therapeutic Guidelines: Antibiotic 16th Ed. (2019)-Aminoglycosides4.

4.3 Contraindications

A hypersensitivity to any aminoglycoside is a contraindication to the use of tobramycin. A history of hypersensitivity or serious toxic reaction to any aminoglycoside may also contraindicate the use of any other aminoglycoside because of the known cross sensitivity of patients to drugs in this class.

4.4 Special Warnings and Precautions for Use

Precautions should be taken for patients with:
abnormal renal function prior to commencement of treatment with Tobra-Day; signs of diminishing renal function whilst undergoing treatment with once daily Tobra-Day; previous vestibular or auditory toxicity due to tobramycin or other aminoglycosides; existing vestibular or auditory dysfunction prior to initiation of Tobra-Day therapy; developing signs of ototoxicity during treatment with Tobra-Day; a history of abnormal renal function; dehydration.
Precaution should be taken for patients with concurrent use of the following drugs: potent diuretics such as ethacrynic acid or frusemide; other aminoglycosides (especially gentamicin); certain cephalosporins; polymyxin B, colistin; cisplatin, vancomycin; ibuprofen; amphotericin B; methoxyflurane.

Nephrotoxicity and ototoxicity.

As with other aminoglycosides, patients treated with Tobra-Day should be kept under close clinical observation because of its inherent potential to cause ototoxicity and nephrotoxicity.

Ototoxicity.

Tobramycin is prone to cause eighth cranial nerve damage; both vestibular and auditory ototoxicity may occur with high, prolonged, set levels of the drug. The auditory changes are usually irreversible, usually bilateral and may be partial or total. The risk of aminoglycoside induced hearing loss increases with the degree of exposure to either high peak or high trough serum concentrations.
During therapy, some patients who develop cochlear damage may not show symptoms that warn of eighth cranial nerve damage, and partial or total bilateral damage may continue to develop even after therapy has been discontinued; therefore eighth nerve function should be carefully and regularly monitored in all patients. Serial audiograms should be obtained in patients that are old enough to be tested. Other manifestations of neurotoxicity include numbness, skin tingling, muscle twitching and convulsions.
Patients should be regularly asked about any hearing or balance problems and told to report such immediately if they occur. It is recommended that CF patients receiving Tobra-Day should undergo routine audiometric testing. High frequency hearing loss precedes hearing loss across speech frequencies5.
Tobra-Day should be immediately discontinued if any sign of ototoxicity is noticed during routine monitoring.
Patients with mitochondrial DNA mutations, particularly the nucleotide 1555 A to G substitution in the 12S rRNA gene may be at higher risk for ototoxicity, even if the patient's aminoglycoside serum levels were within the recommended range. In case of family history of aminoglycoside-induced deafness or known mitochondrial DNA mutations in the 12S rRNA gene, alternative treatments other than aminoglycosides may need to be considered.

Nephrotoxicity.

Renal function should be closely monitored, and the drug discontinued in patients who develop signs of dysfunction during therapy. Tobramycin is selectively concentrated in renal cortical cells and it produces changes in proximal tubules. The drug causes renal impairment characterised by excretion of casts, oliguria, proteinuria and a progressive rise in blood urea and serum creatinine values.
Serum creatinine and creatinine clearance, serum calcium, magnesium, potassium, sodium levels and blood urea nitrogen should also be monitored. For urine, specific gravity and excretion of protein, cells and casts should be observed.
Serum creatinine should be checked, and creatinine clearance calculated (modified Cockcroft-Gault formula as recommended by Australian Therapeutic Guidelines: Antibiotics, Appendix 6)4 before commencing on Tobra-Day and then 2 to 3 times each week or more frequently if renal function is very unstable.
Aminoglycoside induced nephrotoxicity is usually reversible. Rarely, nephrotoxicity may not manifest until the first few days after cessation of therapy.

Use in impaired renal, vestibular and/or auditory function.

Evidence of impairment in renal, vestibular and/or auditory function requires discontinuation of the drug or at least reduction in dose if continuation of therapy is considered essential.
In high risk patients, the serum concentration of tobramycin should be monitored closely. Rising trough levels above 2 microgram/mL may indicate accumulation of the drug in tissues. It is this accumulation, high peak concentrations, dehydration and cumulative doses which may contribute to ototoxicity and nephrotoxicity. Ototoxicity may occur with peak levels lower than 12 microgram/mL.

Neurologic and muscular disorders.

Aminoglycosides should be used with caution in patients suffering from muscular disorders such as myasthenia gravis or parkinsonism, as these drugs may aggravate muscle weakness because of their potential curare-like effect on neuromuscular function.

Allergic reactions.

Administration of tobramycin may result in allergic reaction. Cross allergenicity among aminoglycosides has also been known to occur.

Nonsusceptible organisms.

Therapy with tobramycin may result in overgrowth of nonsusceptible organisms. If overgrowth of nonsusceptible organisms occurs, appropriate therapy should be initiated.

Use during anaesthesia.

Neuromuscular blockade and respiratory paralysis have been reported in cats receiving very high doses of tobramycin (40 mg/kg). The possibility of prolonged or secondary apnoea should be considered if the drug is administered to anaesthetised patients who are concurrently receiving neuromuscular blocking agents such as suxamethonium, tubocurarine or decethonium. This also applies to patients receiving massive transfusions of citrated blood. If neuromuscular blockade occurs, it may be reversed by the administration of calcium salts.

Use in burns patients.

In patients with extensive burns, pharmacokinetics may be altered resulting in reduced serum levels of tobramycin. Dosage should therefore be based on measured serum levels in these patients.

Use in the elderly.

No data available.

Paediatric use.

The use of once daily tobramycin in CF patients less than 5 years of age has not been studied. The indication for Tobra-Day excludes children younger than 5 years of age.

Effects on laboratory tests.

No data available.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Contraindicated drugs.

Potent diuretics.

Do not give tobramycin in conjunction with ethacrynic acid, frusemide or other potent diuretics which may themselves cause ototoxicity or enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue.

Other neurotoxic and/or nephrotoxic agents.

Avoid concurrent or sequential use of other neurotoxic and/or nephrotoxic antibiotics, particularly other aminoglycosides, polymyxin B, colistin, cisplatin and vancomycin, ibuprofen5.

Neuromuscular blocking agents or other medications with neuromuscular blocking activity.

Care is required if other drugs with a neuromuscular blocking action are given concomitantly with aminoglycosides. The neuromuscular blocking properties of aminoglycosides may be sufficient to provoke severe respiratory depression in patients receiving general anaesthetics or opioids.

Amphotericin B.

May produce synergistic renal toxicity.

Methoxyflurane.

May produce additive or synergistic nephrotoxicity. Renal impairment may appear at lower than usual dosage levels of the drug.

Care with use.

Neuromuscular blocking agents or other medication with neuromuscular blocking activity.

Care is required if other drugs with a neuromuscular blocking action are given concomitantly with aminoglycosides. The neuromuscular blocking properties of aminoglycosides may be sufficient to provoke severe respiratory depression in patients receiving general anaesthetics or opioids (also see Use during anaesthesia).

Beta-lactam antibiotics.

Since aminoglycosides have been shown to be incompatible with some beta-lactams in vitro, these antibiotics should be administered separately if both are required. Antagonism in vivo has been reported only in a few patients with severe renal impairment, in whom aminoglycoside activity was diminished.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

Tobramycin doses as great as 100 mg/kg when administered subcutaneously to rats had no adverse effects on fertility or reproduction. Daily subcutaneous administration of tobramycin doses of 20-40 mg/kg to pregnant rabbits caused anorexia, weight loss and renal injury. Fifteen percent of the animals of the 20 mg/kg group and 85 percent of those of the 40 mg/kg group died or aborted. Fetal development appeared normal in these animals at the time of death or abortion. No drug related abnormalities were noted in any of the progeny, despite the maternal toxicity.
(Category D)
Aminoglycosides can cause fetal damage when administered during pregnancy. Aminoglycoside antibiotics cross the placenta and there have been reports of total irreversible bilateral congenital deafness in children whose mothers have received streptomycin or kanamycin during pregnancy. Tobramycin crosses the placenta, distributes to most fetal tissues, and concentrates in fetal kidneys and urine. There have been no reports of teratogenicity after the use of tobramycin in humans although high doses have been reported to cause renal toxicity in pregnant rats, their fetuses and their newborns. Ototoxicity has not been reported as an effect of in utero exposure5.
However, in view of the theoretical risks of aminoglycosides Tobra-Day should only be used in pregnancy if the potential benefit outweighs the potential risk to the fetus.
Category D definition: Drugs which have caused, are suspected to have caused, or may be expected to cause an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Accompanying texts should be consulted for further details.
 Tobramycin is excreted in the breast milk with concentrations of 0.60 and 0.85 microgram/mL at one and eight hours after an intramuscular dose of 80 mg. Because of the potential to the newborn it is recommended that breast feeding be discontinued during therapy with Tobra-Day.

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)

Frequency estimate: very common ≥ 10%; common ≥ 1% to < 10%; uncommon ≥ 0.1% to < 1%; rare ≥ 0.01% to < 0.1%; very rare < 0.01%.

Adverse drug reactions reported in clinical studies with CF patients.

Ototoxic.

Common: high frequency hearing loss. Uncommon: tinnitus.

Vestibular.

Common: acute dizziness, vertigo.

Renal and urinary disorders.

Very common: reduced creatinine clearance indicating reduced renal function. Uncommon: increase in serum creatinine. Rare: interstitial nephritis, acute renal failure.

Immune system disorders.

Rare: respiratory depression, rash, anaphylaxis.
As with other aminoglycosides, ototoxicity and nephrotoxicity can occur. The risk of adverse effects is increased in patients with poor renal function, the elderly, patients on prolonged treatment or with serious underlying pathology.

More common adverse reactions.

Otic.

Ototoxicity occurs as the drug penetrates into the inner ear during periods of high serum concentration. Both auditory and vestibular branches of the eighth cranial nerve may be adversely affected. Ototoxicity initially manifests as vestibular dysfunction with or without loss of high tone activity, similar to that of other aminoglycosides. Symptoms include dizziness, vertigo, tinnitus, roaring in the ears and hearing loss. Hearing loss is usually irreversible. Ototoxic damage may progress in some patients even after the drug is discontinued.

Renal: nephrotoxicity.

Reversible nephrotoxicity may occur and acute renal toxicity and interstitial nephritis have been reported often in association with other drugs which are nephrotoxic (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Decreased glomerular filtration is usually seen only after several days and may even occur after therapy has been stopped. Renal failure characterized by elevated creatinine and urea concentrations appears to be a rare complication of aminoglycoside therapy in patients with CF5.
Patients with pre-existing renal impairment who are treated for longer periods or with higher doses than those recommended are at greater risk. Repeated intravenous aminoglycoside use in CF is associated with long-term renal damage6.
Nephrotoxicity manifests as changes in renal function: rising serum urea, blood urea nitrogen (BUN), nonprotein nitrogen (NPN) and serum creatinine and by oliguria, cylindruria and increased proteinuria. Nephrotoxicity may be increased by the concurrent administration of other drugs (see Section 4.3 Contraindications; Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Patients with pre-existing renal impairment are at greatest risk. Adverse renal effects can occur in patients with initially normal renal function.

Gastrointestinal.

Nausea, vomiting and diarrhoea.

Less common reactions.

Musculoskeletal.

The aminoglycosides are known to possess neuromuscular blocking effects and to be capable of exacerbating impairment of neuromuscular transmission in clinical conditions such as myasthenia gravis or severe hypocalcaemia, or when used in conjunction with nondepolarising neuromuscular relaxants such as d-tubocurarine.
Neuromuscular blockade may result in weakness of skeletal muscles and respiratory depression especially in patients with myasthenia gravis, severe hypocalcaemia or who have recently received other neuromuscular blocking agents. Peritoneal lavage with tobramycin could precipitate apnoea because high concentrations of drug come in contact with the diaphragm. Rarely, blockade has been observed following intramuscular or intravenous injection. Tobramycin is usually safely used prior to surgery if given in recommended single doses.

Dermatological.

Maculopapular rash, urticaria, itching.

Rare reactions.

Biochemical abnormalities.

Some patients with malignant diseases have developed a complex metabolic syndrome of two to eight weeks duration after administration of tobramycin, including hypocalcaemia, hypomagnesaemia, hypokalaemia, hypoalbuminaemia, hypophosphataemia and hypouricaemia. Other reported abnormalities include increased AST, ALT, serum bilirubin and alkaline phosphatase.

Haematological and reticuloendothelial.

Anaemia, granulocytopenia and thrombocytopenia, eosinophilia, decreased platelet and white cell counts.

Immunological.

Fever, rash, itching, urticaria. Adverse effects on the immune response via inhibition of chemotaxis and microbicidal activity of phagocytes have been reported. Angioedema, exfoliative dermatitis, stomatitis and anaphylaxis are hypersensitivity reactions reported with aminoglycosides in general.

Neurological.

Lethargy. Acute brain syndrome has been reported in an elderly patient after four days of therapy with tobramycin. The delirium was reversed after drug discontinuance. Neurotoxicity is rare with tobramycin. Peripheral neuropathy, paraesthesia and muscle weakness have been reported.

Other.

Pain after intramuscular administration and thrombophlebitis after intravenous administration.

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 http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Signs and symptoms.

The severity of the signs and symptoms following a tobramycin overdose are dependent on the dose administered, the patient's renal function, state of hydration and age and whether or not other medications with similar toxicities are being administered concurrently. Neuromuscular blockade or respiratory paralysis may occur following administration of aminoglycosides. Nephrotoxicity, auditory and vestibular toxicity have been associated with aminoglycoside overdose.

Treatment.

In managing overdose, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in the patient.
The initial intervention in a tobramycin overdose is to establish an airway and ensure oxygenation and ventilation. Resuscitative measures should be initiated promptly if respiratory paralysis occurs.
Patients that have received an overdose of tobramycin and have normal renal function should be adequately hydrated to maintain a urine output of 3-5 mL/kg/hr. Fluid balance, creatinine clearance, and tobramycin plasma levels should be carefully monitored.
Patients in whom the elimination half-life is greater than 2 hours or whose renal function is abnormal may require more aggressive therapy. In such patients, haemodialysis may be beneficial.
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: Tobramycin sulfate is a water soluble antibiotic of the aminoglycoside group and is produced by Streptomyces tenebrarius.

Mechanism of action.

Tobramycin is usually active against most strains of the following organisms: Pseudomonas aeruginosa, Escherichia coli, Proteus species (indole positive and indole negative) including Proteus mirabilis, Proteus morganii, Proteus rettgeri and Proteus vulgaris, Klebsiella, Enterobacter, Serratia species; Providencia species and Citrobacter species; Staphylococci, including Staphylococci aureus (coagulase positive and coagulase negative).
Aminoglycosides have a low order of activity against most Gram positive organisms; Enterococci and Streptococci are insensitive.
Aminoglycosides exhibit synergy with antibiotics, such as beta-lactams and vancomycin, which affect the bacterial cell wall and enhance aminoglycoside penetration. In vitro studies have shown that an aminoglycoside combined with an antibiotic that interferes with cell wall synthesis affects some group D streptococcal strains synergistically. The combination of benzylpenicillin and tobramycin results in a synergistic bactericidal effect in vitro against certain strains of S. faecalis. However, this combination is not synergistic against other closely related organisms, e.g. S. faecium. Speciation of group D streptococci alone cannot, therefore, be used to predict susceptibility. Susceptibility testing and tests for antibiotic synergism are recommended.
Anaerobic organisms, yeasts and fungi are resistant to aminoglycosides.
Cross resistance between aminoglycosides occurs and depends largely on inactivation by bacterial enzymes.
Bacterial resistance to tobramycin may occur and cross resistance between aminoglycosides may exist.
Bactericidal activity of aminoglycosides is concentration dependent. This activity is maximized when the serum peak concentration is between 8 and 10 times the MIC. The higher serum concentration of tobramycin with once daily dosing increases the concentration dependent killing of bacteria.

Clinical trials.

A large multicentre, randomised, double blinded, comparative study assessed the safety and efficacy of once daily versus thrice daily tobramycin in CF patients with chronic Pseudomonas aeruginosa infections. The primary endpoint was change in forced expiry volume in 1 second (FEV1)7 during 14 days treatment. A number of safety parameters, including serum creatinine and pure tone audiometry were assessed as secondary endpoints. A total of 244 patients from CF centres in the UK were randomly assigned to once or thrice daily tobramycin (with ceftazidime) for 14 days. 219 completed the treatment. Equivalence was demonstrated for the primary endpoint.

5.2 Pharmacokinetic Properties

Absorption.

Tobramycin is rapidly absorbed following intramuscular injection and peak serum concentrations occur between 30 and 90 minutes after injection. In adults with normal renal function a single intramuscular injection of 1 mg/kg bodyweight will produce maximum serum levels of approximately 4 microgram/mL and are measurable for as long as eight hours. When tobramycin is administered by the intravenous route over a period of one hour serum concentrations are similar to those obtained after intramuscular injection.
Tobramycin is poorly absorbed from the gastrointestinal tract.

Distribution.

After parenteral administration tobramycin can be detected in tissues and body fluids such as sputum, peritoneal fluid, synovial fluid and abscess fluids. Concentrations in bile and stools are normally low suggesting minimal biliary excretion. Tobramycin has appeared in low concentration in the cerebrospinal fluid following parenteral administration, and the concentrations are dependent on dose, rate of penetration and degree of meningeal inflammation.
Patients with CF have both an increased volume of distribution and an increased renal clearance with aminoglycosides. This results in the need for much higher doses of tobramycin than the general population.

Metabolism.

Aminoglycosides do not appear to be metabolised.

Excretion.

Tobramycin is excreted almost exclusively by glomerular filtration. Renal clearance is similar to that of endogenous creatinine. Ultrafiltration studies demonstrate that practically no serum protein binding occurs. In patients with normal renal function up to 84% of the dose is recoverable from the urine in 8 hours and up to 93% in 24 hours. The serum half-life is usually 2-3 hours in adults with normal renal function but in patients with impaired renal function a range from 5 to 70 hours has been reported.

Pharmacokinetics in cystic fibrosis patients.

Following intravenous injection of tobramycin (8 to 12 mg/kg) in glucose injection over 30 minutes, the peak plasma concentration achieved ranges from 30 to 50 mg/L and is obtained in about 30 minutes. There is negligible plasma protein binding. The half-life is approximately 2 to 3 hours in patients with normal renal function but may be shorter in young children with CF.

5.3 Preclinical Safety Data

Genotoxicity.

Tobramycin was found to be negative in the mouse lymphoma forward mutation assay. Tobramycin did not induce chromosomal aberrations in Chinese hamster ovary cells, and was negative in the mouse micronucleus test.

Carcinogenicity.

Long term animal studies have not been performed to evaluate the carcinogenic potential of tobramycin by the intravenous route.

6 Pharmaceutical Particulars

6.1 List of Excipients

Sodium hydroxide, sulfuric acid, water for injections.

6.2 Incompatibilities

Tobramycin injections have been reported to be incompatible with the solutions of the following: alcohol 5%, cefamandole nafate, cefepime HCl, flucloxacillin sodium, heparin sodium, propofol, clindamycin8.
It is recommended that Tobra-Day not be mixed with other drugs.
In addition, the activity of tobramycin appears to be inhibited by calcium and magnesium ions.

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.
After dilution - chemical and physical in use stability has been demonstrated for Tobra-Day concentrated injection for intravenous infusion when diluted in controlled and validated aseptic conditions in a minimum volume of 50 mL of sodium chloride intravenous infusion (0.9% w/v) or 5% glucose intravenous infusion.
Once diluted the solution should be used as soon as possible. If storage is necessary the prepared solution should be refrigerated between 2°C and 8°C and stored for no longer than 24 hours before discarding.

6.4 Special Precautions for Storage

Store at 2°C-8°C. (Refrigerate Do not freeze).
Keep the vial in the carton to protect from light.
After dilution - see Section 6.3 Shelf Life.

6.5 Nature and Contents of Container

Tobra-Day injection is presented in a 7 mL amber glass vial containing 5 mL of solution.
Pack of 10 vials.
AUST R 150481.

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

4-O-(3-amino-3-deoxy-α-d- glucopyranosyl)-2-deoxy-6-O- (2,6-diamino-2,3,6- trideoxy-α-d-ribo- hexopyranosyl)-l-streptamine.
The molecular formula is C18H37N5O9. Its molecular weight is 467.5.

Chemical structure.


CAS number.

32986-56-4.

References

1. M.L. Barclay, C.M.J. Kirkpatrick, E.J. Begg. Once Daily Aminoglycoside Therapy Is It Less Toxic Than Multiple Daily Doses and How Should It Be Monitored. Clin Pharmacokinet 36(2) 89-98 1999.
2. K. P. Coulthard, D. G. Peckham, S. P. Conway, C. A. Smith, J. Bell, and J. Turnidge. Therapeutic drug monitoring of once daily tobramycin in cystic fibrosis-caution with trough concentrations. J.Cyst.Fibros., 2006.
3. S.B. Duffull, C.M.J. Kirkpatrick, E.J. Begg. Comparison of two Bayesian approaches to dose individualization for once daily aminoglycoside regimens. Br J Clin Pharmacol 43:125-135 1997.
4. Australian Therapeutic Guidelines-Antibiotics 2019 version 16.
5. K. H. Tan, M. Mulheran, A. J. Knox, and A. R. Smyth. Aminoglycoside prescribing and surveillance in cystic fibrosis. Am.J.Respir.Crit Care Med. 167 (6):819-823, 2003.
6. M. Al-Aloul, H. Miller, S. Alapati, P. A. Stockton, M. J. Ledson, and M. J. Walshaw. Renal impairment in cystic fibrosis patients due to repeated intravenous aminoglycoside use. Pediatr.Pulmonol. 39 (1):15-20, 2005.
7. A. R. Smyth and K. H. Tan. Once-daily versus multiple-daily dosing with intravenous aminoglycosides for cystic fibrosis. Cochrane.Database.Syst.Rev. 3:CD002009, 2006.
8. Handbook on Injectable Drugs. Lawrence A Tissel American Society of Health-System Pharmacists. 14th Edition.

7 Medicine Schedule (Poisons Standard)

Schedule 4 - Prescription Only Medicine.

Summary Table of Changes