Tobramycin Wockhardt

New Zealand - English - Medsafe (Medicines Safety Authority)

Buy It Now

Active ingredient:
Tobramycin 300 mg
Available from:
Pharmacy Retailing (NZ) Ltd t/a Healthcare Logistics
Dosage:
300 mg/5mL
Pharmaceutical form:
Solution for inhalation
Composition:
Active: Tobramycin 300 mg Excipient: Sodium chloride Sodium hydroxide Sulfuric acid Water for injection
Prescription type:
Prescription
Therapeutic indications:
Tobramycin Wockhardt is indicated for the management of cystic fibrosis patients with P. aeruginosa infections. Safety and efficacy have not been demonstrated in patients under the age of 6 years, patients with FEV1 <25% or >75% predicted, or patients colonised with Burkholderia cepacia.
Product summary:
Package - Contents - Shelf Life: Ampoule, plastic, LDPE, 5 mL - 56 dose units - 36 months from date of manufacture stored at 2° to 8°C (Refrigerate, do not freeze) protect from light 28 days opened stored at or below 25°C protect from light
Authorization number:
TT50-10561
Authorization date:
2019-01-17

New Zealand Consumer Medicine Information

Tobramycin Wockhardt

Tobramycin

300 mg/ 5 mL, Solution for Inhalation

What is in this leaflet

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

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.

All medicines have risks and benefits. Your doctor has weighed the risks of you using

Tobramycin Wockhardt against the benefits they expect it will have for you.

If you have any concerns about using 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 it

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,

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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

Your doctor may have prescribed Tobramycin Wockhardt for another reason.

Ask your doctor if you have any questions about why Tobramycin Wockhardt has

been prescribed for you.

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.

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If you are not sure whether you or your child should start using Tobramycin

Wockhardt, 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 breastfeeding 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.

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Taking other medicines

Tell your doctor if you are taking any other medicines, including medicines that

you buy without a prescription from your pharmacy, supermarket or health

food shop. You should also tell any health professional who is prescribing a

new medication for you that you are taking Tobramycin Wockhardt.

Some medicines may interfere with Tobramycin Wockhardt .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 or pharmacist has more information on medicines to be careful with or

avoid while taking 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.

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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

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:

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nebuliser top

nebuliser cup

inspiratory valve cap

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.

10. Connect one end of the tubing to the compressor air outlet. Make sure that the

tubing fits snugly. Plug the compressor into the electrical outlet.

11. Open the Tobramycin Wockhardt ampoule by holding the bottom tab with one

hand and twisting off the top with your other hand.

12. Squeeze all the contents of the ampoule into the nebuliser cup.

13. Replace the nebuliser top (a), put the mouthpiece (d) and the inspiratory valve

cap (c) in place on the nebuliser, and then connect the compressor as

indicated in your nebuliser leaflet.

14. Turn on the compressor. Check that there is a steady mist coming from the

mouthpiece. If there is no mist, check all tubing connections and that the

compressor is working properly.

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

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

normally, but only through your mouth (you may use a nose clip if your doctor

agrees). Try not to block the airflow with your tongue.

17. 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.

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How long to take 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 take 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 13 11 26 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.

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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.

If 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 and pharmacist

that you are taking 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.

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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.

In case of overdose

If you take too much (overdose)

Immediately telephone your doctor or the National Poisons Centre (telephone 0800

POISON or 0800 764 766), or go to accident and emergency at your nearest

hospital, if you think that you or anyone else may have taken too much Tobramycin

Wockhardt.

The telephone numbers are:

Australia: - 13 11 26

New Zealand: - 0800 POISON or 0800 764 766

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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.

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 adverse effects.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor if you notice any of the following and they 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

increased quantity of the substance you cough up (sputum)

Reduced appetite.

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NEW ZEALAND DATA SHEET

1

PRODUCT NAME

TOBRAMYCIN WOCKHARDT Tobramycin 300 mg/5 mL, Solution for inhalation.

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 5 mL ampoule contains a sterile solution of tobramycin 300 mg

For the full list of excipients, see

Section 6.1 List of excipients

3

PHARMACEUTICAL FORM

Solution for inhalation.

TOBRAMYCIN WOCKHARDT 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.

4

CLINICAL PARTICULARS

4.1

THERAPEUTIC INDICATIONS

TOBRAMYCIN WOCKHARDT injection 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 >75% predicted, or patients

colonised with

Burkholderia

cepacia

(see Section 5.1 Pharmacodynamic properties: Clinical

trials)

4.2 DOSE AND METHOD OF ADMINISTRATION

Dosage

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. Dosage is not adjusted

by weight. All patients should be administered 300 mg twice daily. The doses should be taken

as close to 12 hours apart as possible; they should not be taken less than six hours apart.

tobramycin is inhaled while the patient is sitting or standing upright and breathing normally

through the mouthpiece of the nebuliser. Nose clips may help the patient breathe through the

mouth.

Tobramycin is administered twice daily in alternating periods of 28 days. After 28 days of

therapy, patients should stop tobramycin therapy for the next 28 days, and then resume

therapy for the next 28 days on/28 days off cycle.

Method of administration

TOBRAMYCIN WOCKHARDT is supplied as a single-use ampoule and is administered by

inhalation, over a 10 to 15 minute period, using a hand-help PARI LC PLUS reusable

nebuliser

with

DeVilbiss

PulmoAide

compressor.

TOBRAMYCIN

WOCKHARDTwith nebulizers other than the PARI LC PLUS has not been adequately

studied.

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TOBRAMYCIN

WOCKHARDT

subcutaneous,

intravenous

intrathecal

administration.

TOBRAMYCIN WOCKHARDT should not be diluted or mixed with dornase alfa or other

medications in the nebuliser.

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.

4.3 CONTRAINDICATIONS

Tobramycin

contraindicated

patients

with

known

hypersensitivity

aminoglycoside.

4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Tobramycin is not for subcutaneous, intravenous or intrathecal administration.

Caution should be exercised when prescribing tobramycin to patients with known or

suspected renal, auditory, vestibular, or neuromuscular dysfunction. Patients receiving

concomitant

parenteral

aminoglycoside

therapy

should

monitored

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 during pregnancy, or become pregnant while taking

tobramycin should be apprised of the potential hazard to the foetus.

Ototoxicity

In clinical studies 4 (1%) patients reported mild to moderate hearing loss in clinical studies

of up to 9 treatment cycles. Hearing loss was transient for 3 patients and ongoing at the end

study

patient.

Three

these

patients

received

aminoglycosides

concomitantly to receiving tobramycin. In postmarketing experience, some patients receiving

tobramycin and extensive previous or concomitant parenteral aminoglycosides have reported

hearing loss. 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 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.

If a patient reports tinnitus or hearing loss during tobramycin therapy, the physician should

refer them for audiological assessment.

If ototoxicity occurs in a patient receiving tobramycin tobramycin therapy should be

discontinued until tobramycin serum concentrations fall below 2 µg/mL.

Also see SECTION 4.4 SPECIAL

WARNINGS AND PRECAUTIONS FOR USE -

Laboratory Tests: serum concentrations.

Nephrotoxicity

Nephrotoxicity was not seen during tobramycin clinical studies but has been associated with

aminoglycosides as a class. Nephrotoxicity has been reported with the use of parenteral

aminoglycosides. If nephrotoxicity occurs in a patient receiving tobramycin, tobramycin

therapy should be discontinued until serum concentrations fall below 2 mcg/ml.

Also see SECTION 4.4 SPECIAL WARNINGS AND PRECAUTIONS FOR USE -

Laboratory Tests: serum concentrations.

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Laboratory tests of renal function should be monitored as clinically appropriate.

Muscular Disorders

Tobramycin

should

used

cautiously

patients

with

muscular

disorders,

such

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. In clinical studies of tobramycin, changes in FEV measured after the inhaled

dose were similar in the tobramycin and placebo groups. Bronchospasm should be treated as

medically appropriate.

Laboratory Tests

Audiograms

Clinical studies of tobramycin did not identify hearing loss using audiometric tests which

evaluated hearing up to 8000 Hz. 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

patients

with

normal

renal

function

treated

with

tobramycin,

serum

tobramycin

concentrations are approximately 1 mcg/mL one hour after dose administration and do not

require routine monitoring. 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 of tobramycin 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 Undesirable effects). Laboratory tests of urine and renal

function should be conducted at the discretion of the treating physician.

Animal Toxicology

Bronchoepithelial

hyperplasia

chronic

interstitial

inflammation

around

terminal

bronchioles occurred in studies in rats after daily inhalational exposures to tobramycin for 6

months. Progression of the hyperplastic lesions is currently uncertain and this will be assessed

further in a 2 year inhalational study in progress.

Carcinogenesis

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 hours per day for 95 weeks.

Serum levels of tobramycin of up to 35 µg/mL were measured in rats. There was no drug-

related increase in the incidence of any variety of tumour.

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Mutagenicity

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

induce

chromosomal

aberrations in Chinese hamster ovary cells, and was negative in the mouse micronucleus test.

Characteristics in special population

Paediatric Use

The safety and efficacy of tobramycin have not been studied in paediatric patients under 6 years

of age.

Patients with renal impairment

Tobramycin is primarily excreted unchanged in the urine and renal function is expected to

affect the exposure to tobramycin. See PRECAUTIONS - Nephrotoxicity.

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.

4.5

INTERACTIONS WITH OTHER MEDICINES AND OTHER FORMS OF

INTERACTION

No clinical drug interaction studies have been performed with tobramycin. However, in

clinical studies of tobramycin, patients taking tobramycin concomitantly with dornase alfa,

[3-agonists,

inhaled

corticosteroids,

other

anti-pseudomonal

antibiotics,

parenteral

aminoglycosides

demonstrated adverse experience profiles similar to the study population as a whole.

Concurrent

and/or

sequential

tobramycin

with

other

drugs

with

neurotoxic,

nephrotoxic,

ototoxic

potential

should

avoided.

Some

diuretics

enhance

aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue. Tobramycin

should

administered

concomitantly

with

ethacrynic

acid,

frusemide,

urea,

intravenous mannitol.

4.6

FERTILITY, PREGNANCY AND LACTATION

Effects on fertility

No reproduction toxicology studies have been conducted with tobramycin administered by

inhalation. Data in animals from subcutaneous administration of tobramycin did not reveal a

problem or potential problem concerning fertility in either males or females. Subcutaneous

administration of up to 600 mg/m

/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.

Use in pregnancy

Category D. There are no adequate data from the use of tobramycin administered by

inhalation in pregnant women. No reproduction toxicology studies have been conducted with

tobramycin. However, subcutaneous administration of tobramycin at doses of 600 or 220

mg/m

/day during organogenesis was not teratogenic in rats or rabbits, respectively. Doses of

tobramycin = 440 mg/m

/day were severely maternally toxic to rabbits and precluded the

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evaluation

teratogenicity.

Aminoglycosides

cause

foetal

harm

(eg.

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.

Use in Lactation

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

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

Patients should be warned about the potential for nervous system such as dizziness and

somnolence, and advised not to drive or operate machinery if these symptoms occur or until

their individual susceptibility is known.

4.8 UNDESIRABLE EFFECTS

Tobramycin 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

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 -treated patients. Thirty-three patients (13%) treated with tobramycin 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 group (3%) reported tinnitus

compared to no placebo patients.

All episodes were transient, resolved without discontinuation of the tobramycin 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 and placebo groups.

Nine (3%) patients in the tobramycin 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.

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Table 1 lists the percent of patients with treatment-emergent adverse experiences that

occurred in = 5% 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 during the first

three cycles of therapy.

Table 1: Percent of Patients with Treatment-Emergent Adverse Events Occurring

in ≥ 5%of Patients in Any Group

During the Open Label

Extension

a

During the Placebo-

Controlled Studies

Adverse Event

9 Cycles

(n = 192)

6 Cycles

(n = 204)

3 Cycles

(n = 258)

Placebo

(n = 262)

Respiratory System

Cough Increased

Pharyngitis

Sputum Increased

Dyspnea

Rhinitis

Lung Disorder

Hemoptysis

Asthma

Lung Function Decreased

Sputum Discoloration

Upper Respiratory Tract Infection

Sinusitis

Voice Alteration

Epistaxis

Lower Respiratory Tract Infection

Respiratory Disorder

Hyperventilation

Hypoxia

Nasal Polyp

Laryngitis

Body as a Whole

Fever

Asthenia

Chest pain

Headache

Abdominal Pain

Pain

Back Pain

Chills

Accidental Injury

Malaise

Flu Syndrome

Digestive System

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Anorexia

Vomiting

Nausea

Diarrhoea

Dyspepsis

Oral Moniliasis

Hemic and lymphatic system

Lymphadenopathy

Metabolic & nutritional disorders

Weight loss

Skin and Appendages

Rash

Sweating

Special senses

Ear pain

Ear disorder

Otitis media

Hemic and Lymphatic system

Lymphadenopathy

Nervous system

Dizziness

Somnolence

Musculoskeletal System

Myalgia

Patients with newly-occurring or worsening adverse events since Week 24.

The 6-Cycle group received Placebo during the controlled study (first 3 cycles).

The 9-Cycle group received tobramycin during both the controlled study and the open label extension

Postmarketing Experience

Some

patients

receiving

tobramycin

extensive

previous

concomitant

parenteral

aminoglycosides

have

reported

hearing

loss

during

postmarketing

surveillance

(see

PRECAUTIONS).

Adverse drug reactions from spontaneous reports and literature cases (frequency not

known)

The following adverse drug reactions have been derived from post marketing experience with

tobramycin 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

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Aphonia, dysgeusia

Respiratory, thoracic, and mediastinal disorders

Bronchospasm, oropharyngeal pain, sputum increased, chest pain

General disorders and administration site conditions

Decreased appetite

{Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It

allows continued monitoring of the benefit/risk balance of the medicine. Healthcare

professionals are asked to report any suspected adverse reactions

https://nzphvc.otago.ac.nz/reporting/}

4.9

OVERDOSE

Signs and symptoms

In the event of inadvertent administration of tobramycin by the IV route, signs and symptoms

of parenteral tobramycin overdosage may occur that include dizziness, tinnitus, vertigo, loss

high-tone

hearing

acuity,

respiratory

distress

failure,

renal

impairment,

neuromuscular blockade. Administration by inhalation results in low systemic bioavailability

of tobramycin.

In the event of accidental oral ingestion of tobramycin, systemic toxicity is unlikely as

tobramycin is not significantly absorbed following oral administration.

The maximum tolerated daily dose of tobramycin has not been established. Tobramycin serum

concentrations may be helpful in monitoring overdose.

Treatment

cases

suspected

overdosage,

physicians

should

contact

National

Poisons

Information Centre on telephone 0800 POISON or 0800 764 766 for information about advice

on management. In the case of any overdosage, the possibility of drug interactions with

alterations in drug disposition should be considered. Acute toxicity should be treated with

immediate withdrawal of tobramycin, and baseline tests of renal function should be undertaken.

Haemodialysis may be helpful in removing tobramycin from the body.

5 PHARMACOLOGICAL PROPERTIES

5.1 PHARMACODYNAMIC PROPERTIES

Pharmacotherapeutic group:

Aminoglycoside antibacterials,

ATC code: J01GB01

Microbiology

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

. It is bactericidal at concentrations equal to-or slightly greater than

inhibitory concentrations.

Susceptibility Testing

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A single sputum sample from a cystic fibrosis patient may contain multiple morphotypes of

Pseudomonas aeruginosa

and each morphotype may have a different level of

in vitro

susceptibility to tobramycin. Treatment for 6 months with tobramycin in two clinical studies

did not affect the susceptibility of the majority of

P. aeruginosa

isolates tested; however,

increased MICs were noted in some patients. The clinical significance of this information has

not been clearly established in the treatment of

P. aeruginosa

in cystic fibrosis patients. For

additional information regarding the effects of tobramycin on

P. aeruginosa

MIC values and

bacterial sputum density, please refer to the CLINICAL TRIALS section.

in vitro

antimicrobial susceptibility test methods used for parenteral tobramycin therapy

can be used to monitor the susceptibility of

P. aeruginosa

isolated from cystic fibrosis 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 aerosolised

administration of tobramycin. The relationship between in vitro susceptibility test results and

clinical outcome with tobramycin therapy is not clear.

Clinical trials

identically

designed,

double-blind,

randomised,

placebo-controlled,

parallel

group,

24week 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 (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

parenteral

anti-pseudomonal

therapy,

132-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

tobramycin therapy 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

placebo-controlled

studies,

tobramycin

treated

patients

experienced

significant

improvement in pulmonary function. Improvement was demonstrated in the tobramycin group

in Study 1 by an average increase in FEV% predicted of about 11% relative to baseline (Week

0) during 24 weeks compared to no average change in placebo patients. In Study tobramycin

treated patients had an average increase of about 7% compared to an average decrease of about

1% in placebo patients.Three hundred and 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, 3 cycles during the controlled studies and 6 cycles during the open label

extension. At the end of cycle 9, in these patients

% 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. Whilst on placebo, these patients experienced a

mean 2.9% decrease in % predicted had improved to 1% below baseline.

P. aeruginosa

density in sputum was measured during the 24-week placebo-controlled studies.

tobramycin therapy 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.

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

Version 1.0 11 Dec 2018

Page 10

tobramycin were

hospitalised for an average of 5.1 days compared to 8.1 days for placebo

patients. Patients

treated with tobramycin 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 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 antipseudomonal antibiotics.

relationship

between

vitro

susceptibility

test

results

clinical

outcome

with

tobramycin therapy is not clear. However, four tobramycin patients who began the clinical trial

with

P.aeruginosa

isolates

having

values

2:128

I-Ig/mL

experience

improvement in FEV, 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

P.aeruginosa

with an MIC = 16 µg/mL increased from 13.7% at baseline 5 to 29.8% at the

end of cycle 9. The proportion of patients with isolates of

P. aeruginosa

with MIC = 128 µg/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.

Treatment for 18 months (9 cycles) with tobramycin in clinical studies demonstrated a trend to

decreasing in vitro susceptibility of

P. aeruginosa

isolates. The clinical significance of this

information has not been clearly established in the treatment of

P. aeruginosa

in cystic fibrosis

patients.

The safety and efficacy of tobramycin have not been studied in paediatric patients under 6 years

of age.

5.2 PHARMACOKINETIC PROPERTIES

TOBRAMYCIN WOCKHARDT contains tobramycin, a cationic polar molecule that does not

readily cross epithelial membranes. The bioavailability of tobramycin may vary because of

individual

differences

nebuliser

performance

airway

pathology.

Following

administration of tobramycin, tobramycin remains concentrated primarily in the airways.

Sputum Concentrations

Ten minutes after inhalation of the first 300 mg dose of tobramycin, the average concentration

of tobramycin was 1237 mcg/g (ranging from 35 to 7414 mcg/g) in sputum. Tobramycin does

not accumulate in sputum. After 20 weeks of therapy with the tobramycin regimen, the average

concentration of tobramycin at ten minutes after inhalation as 1154 mcg/g (ranging from 39 to

8085 mcg/g) in sputum. High variability of tobramycin concentration in sputum was observed.

hours

after

inhalation,

sputum

concentrations

declined

approximately

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 by cystic fibrosis patients was 0.95 mcg/mL. After 20 weeks of therapy on

the tobramycin regimen, the average serum tobramycin concentration one hour after dosing

was 1.05 g/mL.

Elimination

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