Tobramycin 40mg/Ml Solution For Injection Or Infusion
Package leaflet: Information for the user
Tobramycin 40 mg/ml, Solution for Injection or Infusion
Tobramycin
The name of your medicine is ‘Tobramycin 40 mg/ml, Solution for Injection or Infusion’ but in the rest of the leaflet, it shall be referred to as ‘Tobramycin’.
Read all of this leaflet carefully before you start using this medicine because it contains important information for you.
- Keep this leaflet. You may need to read it again.
- If you have any further questions, ask your doctor, pharmacist or nurse.
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
- If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet. See section 4.
What is in this leaflet
1. What Tobramycin is and what it is used for
2. What you need to know before you use Tobramycin
3. How to use Tobramycin
4. Possible side effects
5. How to store Tobramycin
6. Contents of the pack and other information
1. What Tobramycin is and what it is used for
This medicine contains the active ingredient tobramycin .
Tobramycin is an antibiotic medicine (used to fight infections caused by bacteria) in the form of a solution for injection or infusion.
This medicine can be used to treat infections of the:
• brain
• stomach and intestines
• bladder or kidney (urinary tract infections)
• lungs (lower respiratory tract infections)
• skin and soft tissue, including burns.
Tobramycin may also be considered in serious staphylococcal infections for which penicillin or other less potentially toxic medicines cannot be used.
2. What you need to know before you use Tobramycin
Do not use Tobramycin:
• if you are allergic to tobramycin, other aminoglycosides or to any of the other ingredients of this medicine (listed in section 6).
• if you are pregnant or breast-feeding (see section “Pregnancy, breast-feeding and fertility”).
Warnings and precautions
Talk to your doctor, pharmacist or nurse before using Tobramycin:
• if you have kidney problems (renal impairment) or if you notice any signs of problems with your kidney during therapy.
• if you have existing hearing problems (including noises in the ears and dizziness) or if you notice any change in your hearing during treatment, as risk of hearing loss caused by aminoglycosides increases when you receive higher dose.
• if you are an elderly patient or suffer from an excessive loss of body fluids (dehydration).
• if you suffer from muscle disorders such as muscle weakness (myasthenia gravis) and nerve-related muscle disease (Parkinson's disease), as symptoms related to these conditions may worsen over time.
• Because tobramycin and other aminoglycosides can be toxic to nervous tissue (neurotoxicity), especially ear (ototoxicity) and kidney (nephrotoxicity), your doctor will monitor you closely during treatment and change the dose if necessary.
• There is a risk of inability to sleep for a longer duration if tobramycin is given to:
- patients who are being treated for anaesthesia while using muscle relaxants (neuromuscular-blocking agents), such as succinylcholine, tubocurarine or decamethonium
- patients who have received blood transfusion of citrated blood.
Other medicines and Tobramycin
Tell your doctor if you are using, have recently used or might use any other medicines, including
medicines obtained without a prescription. This is because Tobramycin can affect the way some
medicines work and some medicines can have an effect on Tobramycin.
In particular, tell your doctor or pharmacist if you are using any of the following medicines:
• other antibiotics such as amikacin, streptomycin, neomycin, kanamycin, gentamicin, paromomycin, amphotericin B, cephaloridine, viomycin, polymyxin B, colistin, cisplatin, vancomycin. Use of any of these medicines together with Tobramycin should be avoided.
• some diuretics and cisplatin cause ear toxicity (ototoxicity) and should not be given together with Tobramycin.
• furthermore, an increased incidence of kidney toxicity (nephrotoxicity) has been observed following co-administration of aminoglycosides, cyclosporins, cephalosporins (antibacterials) and cisplatin.
• muscle relaxants cause difficulty in breathing (respiratory paralysis) which can be severe if given together with Tobramycin.
• Tobramycin increases the effect of other medicines such as warfarin and phenindione.
• Tobramycin is known to reduce the effect of other medicines such as neostigmine and pyridostigmine.
In patients who have severe kidney problems, P-lactam antibiotics have been found to be able to inactivate tobramycin and other aminoglycosides.
Pregnancy, breast-feeding and fertility
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before using this medicine.
Tobramycin should not be used during pregnancy as harm to an unborn child, such as deafness, can occur when this medicine is given by an injection.
Tobramycin can be transferred to breast milk, and should not be used during breast-feeding. Your doctor will decide whether to discontinue breast-feeding or to stop the treatment with Tobramycin.
Fertility
The effect of tobramycin on fertility is unknown.
Driving and using machines
This medicine is not likely to affect your ability to drive or use machines. However, side effects such as dizziness or drowsiness may occur. Do not drive or use machines if this happens to you while you are being treated with Tobramycin.
Tobramycin contains sodium bisulphite
This medicine contains sodium bisulphite, which may rarely cause severe allergic type (hypersensitivity) reactions (skin rash, swelling of eyelids, face or lips) and difficulty in breathing or wheezing (bronchospasm). This is rare but you may be more at risk if you suffer from allergies or asthma.
This medicine contains less than 1 mmol sodium per dose of Tobramycin, that is essentially sodium free.
3. How to use Tobramycin
Dosage
A doctor or nurse will give you Tobramycin into one of your muscles (intramuscularly) or into one of your veins (intravenously).
Your doctor will work out the correct dose of Tobramycin for you and how often it must be given. The dose will depend on your medical condition, your size, how serious the infection is, your age and how well your kidneys are working.
Your doctor will tell how well your kidneys are working using blood or urine samples.
Adults:
3 mg per kg of body weight every 24 hours, given as 3 doses of 1 mg per kg of body weight every 8 hours. If you have a serious bacterial infection, your doctor may use larger doses.
Children:
6 to 7.5 mg per kg of body weight every 24 hours, given as 3 or 4 equal doses.
Premature or new-born babies:
Up to 4 mg per kg of body weight every 24 hours, given as 2 equal doses every 12 hours.
Use in children
This medicine should be used with caution in premature infants and infants, as kidney function in these children is not fully developed.
Use in patients with impaired kidney function
If you have a kidney disorder, your doctor will reduce your dose. This may happen during your treatment.
The usual length of treatment is 7 to 10 days. If you are treated for longer than this, your doctor will need to test your kidneys and ears because they may be damaged by the treatment.
If you use more Tobramycin than you should
As this medicine will be given to you whilst you are in hospital it is unlikely that you will be given too little or too much; however, tell your doctor or pharmacist if you have any concern about how much medicine you have been given or how often you have been given it.
In case of an overdose you may experience: impaired hearing, dizziness, tinnitus (ringing in the ears) or kidney damage.
In severe cases, neuromuscular blockade may occur. In addition, liver damage has also been reported.
If you stop using Tobramycin
This can worsen your condition. Discontinuation of the treatment is not recommended, even if you begin to feel better again.
If you have any further questions on the use of this medicine, ask your doctor, pharmacist or nurse.
Like all medicines, this medicine can cause side effects, although not everybody gets them. Serious Side Effects
If you notice any of the following rare but serious side effects, stop using this medicine and contact a doctor immediately:
• Hearing loss, which may progress to deafness
• Acute kidney failure
• Coughing, aching, headaches, feverishness, vomiting, diarrhoea followed by a red rash across the face and body with blisters in the nose, mouth, eyes and genital areas, as these may be symptoms of life threatening skin diseases called Stevens-Johnson syndrome or toxic epidermal necrolysis.
Other Side Effects
Common (may affect up to 1 in 10 people)
• Eosinophilia (an increase in one type of white blood cells).
• Hearing loss, dizziness, vertigo, ringing in the ear (tinnitus) in patients with kidney problems (renal impairment).
• Thrombophlebitis (vein inflammation related to a blood clot).
• Increase of enzymes (transaminases).
• Kidney function changes in patients with kidney problems (renal impairment).
• Pain and local reactions at the injection site.
Uncommon (may affect up to 1 in 100 people)
• Headache.
• Hearing loss, dizziness, vertigo, ringing in the ears (tinnitus) in patients with normal kidney function.
• Vomiting, discomfort.
• Liver function changes (increase of alkaline phosphatase, lactate dehydrogenase and bilirubin).
• Skin rash (exanthema), hives (urticaria) and itching (pruritus).
• Kidney function changes in patients with normal kidney function.
Rare (may affect up to 1 in 1000 people)
• Anemia, decrease in the number of white blood cells (granulocytopenia, leukopenia), decrease in the number of platelets (thrombocytopenia).
• Decreased serum calcium, magnesium, sodium and potassium.
• Mental confusion, disorientation.
• Diarrhoea.
• Fever, abnormal drowsiness (lethargy).
Not known (frequency cannot be estimated from the available data)
• Numbness, prickly sensation in the skin.
• Twitching muscles, spasms.
Reporting of side effects
If you get any side effects talk to your doctor, pharmacist or nurse. This includes any possible side effects not listed in this leaflet.
You can also report side effects directly via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard. By reporting side effects you can help provide more information on the safety of this medicine.
5. How to store Tobramycin
Keep this medicine out of the sight and reach of children.
All vials should be kept in the outer carton to protect from light.
Do not use this medicine after the expiry date which is stated on the vial label and carton, after ‘EXP.’. The expiry date refers to the last day of that month.
This medicinal product does not require special storage conditions.
Chemical and physical in-use stability has been demonstrated in dextrose 5% w/v and sodium chloride 0.9% w/v infusion solutions for 48 hours at 25°C.
From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2-8°C, unless dilution has taken place in controlled and validated aseptic conditions.
6. Contents of the pack and other information What Tobramycin contains
- The active substance is Tobramycin .
Each ml of solution for injection or infusion contains Tobramycin sulfate equivalent to 40 mg of Tobramycin.
- The other ingredients are: Disodium edetate, Sodium bisulfite (E222), Sulfuric Acid, Sodium hydroxide and Water for injections.
What Tobramycin looks like and contents of the pack
Tobramycin solution for Injection or Infusion is a clear, colourless solution in 2mL/13 mm Tubular Type I flint vial fitted with dark grey bromobutyl serum stopper and 13 mm Electric blue flip off aluminium seal.
Pack size: 10’s x 80mg/2 ml vial
Each 2 ml vial contains 80 mg of Tobramycin.
Not all pack sizes may be marketed
Marketing Authorization Holder
Mylan, Potters Bar, Hertfordshire, EN6 1TL, UK
Manufacturer
Agila Specialties Polska Sp.z.o.o.
10, Daniszewska Str.
03-230 Warsaw Poland
The leaflet was last revised in 10/2014.
TECHNICAL LEAFLET
Tobramycin 40 mg/ml Solution for Injection or Infusion
This is an extract from the Summary of Product Characteristics (SmPC) to assist in the administration of Tobramycin Injection. When determining appropriateness of use in a particular patient, the prescriber should be familiar with the full SmPC.
For intravenous or intramuscular use
Incompatibilities
This medicine should not be mixed with other medicinal products except ingredients used in manufacture of Tobramycin injection.
Preparation Instructions
For intravenous infusion, tobramycin may be diluted with 0.9% sodium chloride (salt solution) or 5% dextrose (sugar solution) and given as a slow injection via a drip over a period of 20 to 60 minutes for adult doses. The volume of diluent for a child's dose should be proportionally less than that for an adult dose.
Dosage and Administration
Tobramycin injection may be given intramuscularly and intravenously. The same dose is recommended for both routes of administration.
It is recommended that both peak and trough serum levels should be determined whenever possible to ensure the correct dosage is given. Blood levels should always be determined in patients with chronic infections such as cystic fibrosis, or where longer duration of treatment may be necessary, or in patients with decreased renal function.
Patients with normal renal function:
Adults: The usual recommended dosage for adults with serious infections is 3 mg/kg/day, administered in three equal doses every eight hours (Table 1). For life-threatening infections, dosages up to 5 mg/kg/day may be administered in three or four equal doses. The dosage should be reduced to 3 mg/kg/day as soon as clinically indicated. To prevent increased toxicity due to excessive blood levels, dosage should not exceed 5mg/kg/day unless serum levels are monitored (see section 4.4).
To achieve therapeutic serum levels in patients with cystic fibrosis, it may be necessary to administer up to 8 to 10 mg/kg/day in equally divided doses. Because serum concentrations of tobramycin vary from one patient to another, serum levels should be monitored.
Table 1: DOSAGE SCHEDULE GUIDE FOR ADULTS WITH NORMAL RENAL FUNCTION (Dosage at 8-Hour Intervals)
|
Patient Weight kg |
Usual dose for serious infections 1 mg/kg q 8 h (total 3 mg/kg/day) |
Maximum dose for life-threatening infections (reduce as soon as possible) 1.66 mg/kg q 8 h (total 5 mg/kg/day unless monitored) | ||
|
mg/dose |
ml/dose* |
mg/dose |
ml/dose* | |
|
120 |
120 |
3.0 |
200 |
5.0 |
|
100 |
100 |
2.5 |
166 |
4.0 |
|
80 |
80 |
2.0 |
133 |
3.0 |
|
60 |
60 |
1.5 |
100 |
2.5 |
|
40 |
40 |
1.0 |
66 |
1.6 |
*Applicable to 40 mg/ml product forms.
In adults with normal renal function, mild to moderate infections of the urinary tract have responded to a dosage of 2-3 mg/kg/day administered as a single intramuscular injection.
Older people: As for adults, but see recommendations for patients with impaired renal function.
Children: The recommended dosage is 6-7.5 mg/kg/day, administered in three or four equally divided doses. In some patients it may be necessary to administer higher doses.
Premature or full-term neonates: Dosages of up to 4 mg/kg/day may be administered in two equal doses every 12 hours, for those between 1.5 and 2.5 kg body weight.
The usual duration of treatment is 7 to 10 days. A longer course of therapy may be necessary in difficult and complicated infections. In such cases, monitoring of renal, auditory and vestibular functions is advised, because neurotoxicity is more likely to occur when treatment is extended for longer than 10 days.
Obese patients: The appropriate dose may be calculated using the patient's estimated lean body weight, plus 40% of the excess, as the weight on which to determine mg/kg.
Patients with impaired renal function: Following a loading dose of 1 mg/kg, subsequent dosage in these patients must be adjusted, either with lower doses administered at eight-hour intervals or with normal doses at prolonged intervals (Table 2). Both of these regimens are suggested as guides to be used when serum levels of tobramycin cannot be measured directly. They are based on either the creatinine clearance or the serum creatinine of the patient, because these values correlate with the half-life of tobramycin. Neither regimen should be used when dialysis is being performed.
Reduced dosage at eight-hour intervals (Regimen I): An appropriately reduced dosage range can be found in the accompanying table (Table 2) for any patient for whom the blood urea, creatinine clearance or serum creatinine values are known. The choice of dose within the indicated range should be based on the severity of the infection, the sensitivity of the pathogen, and individual patient considerations, especially renal function. An alternative rough guide for determining reduced dosage at eight-hour intervals (for patients whose steady-state serum creatinine values are known) is to divide the normally recommended dose by the patient's serum creatinine value (mg/100ml).
Normal dosage at prolonged intervals (Regimen II): Recommended intervals between doses are given in the accompanying table (Table 2). As a general rule, the dosage frequency in hours can be determined by multiplying the patient's serum creatinine level (mg/100ml) by six.
The dosage schedules derived from either method should be used in conjunction with careful clinical and laboratory observations of the patient and should be modified as necessary (see section 4.4).
Table 2: TWO MAINTENANCE REGIMENS BASED ON RENAL FUNCTION AND BODY WEIGHT FOLLOWING AN INITIAL DOSE OF 1 MG/KG*
|
Renal function! |
Regimen I or |
Regimen II | |||||
|
Adjusted doses at 8-hour intervals |
Normal dosage at prolonged intervals | ||||||
|
Blood urea |
Serum creatinine |
Creatinine clearance |
Weight |
Weight/Dose 50-60kg: 60mg 60-80kg: 80mg | |||
|
mg/100 ml |
mmol/l |
mg/100 ml |
mcmol/l |
ml/min |
50-60 kg |
60-80 kg | |
|
Normal: | |||||||
|
<42 |
<7.0 |
<1.3 |
<114.9 |
>70 |
60 mg |
80 mg |
q 8 h |
|
42-74 |
7.0 12.3 |
1.4-1.9 |
123.8-168 |
69-40 |
30-60 mg |
50-80 mg |
q 12 h |
|
75-105 |
12.5 17.5 |
2.0-3.3 |
176.8-291.7 |
39-20 |
20-25 mg |
30-45 mg |
q 18 h |
|
106-140 |
17.7 23.3 |
3.4-5.3 |
300.6-468.5 |
19-10 |
10-18 mg |
15-24 mg |
q 24 h |
|
141-160 |
23.5 26.7 |
5.4-7.5 |
477.4-663 |
9-5 |
5-9 mg |
7-12 mg |
q 36 h |
|
>160 |
>26.7 |
>7.6 |
>671.8 |
<4 |
2.5-4.5 mg |
3.5-6 mg |
q 48 h§ |
*For life-threatening infections, dosages 50% above those normally recommended may be used. The dosages should be reduced as soon as possible when improvement is noted.
fIf used to estimate degree of renal impairment, blood urea and serum creatinine concentrations should reflect a steady state of renal uraemia.
§When dialysis is not being performed.
Following IM administration of a single dose of tobramycin of l mg/kg in adults with normal renal function, peak plasma tobramycin concentrations averaging 4-6 micrograms/ml are attained within 30-90 minutes; plasma concentrations of the drug are 1 microgram/ml or less at 8 hours. Following intravenous infusion of the same dose over 30-60 minutes, similar plasma concentrations of the drug are obtained.
In neonates, average peak plasma tobramycin concentrations of about 5 micrograms/ml are attained 30-60 minutes after a single IM dose of 2 mg/kg; plasma concentrations average 1-2 micrograms/ml at 12 hours.
Warnings
Tobramycin injection contains sodium bisulphite which may rarely cause severe hypersensitivity reactions and bronchospasm, in certain susceptible people. The overall prevalence of sulphite sensitivity in the general population is unknown and probably low, but it occurs more frequently in asthmatic patients.
This drug contains less than 1 mmol (22 mg) sodium per dose, that is it is essentially sodium free.
Patients treated with tobramycin should be under close observation because tobramycin and other aminoglycoside antibiotics have an inherent potential for causing nephrotoxicity and ototoxicity.
Both vestibular and auditory ototoxicity can occur. The auditory changes are irreversible, are usually bilateral, and may be partial or total. Eighth cranial nerve impairment may develop in patients with pre-existing renal damage and if tobramycin is administered for longer periods or in higher doses than those recommended. Other manifestations of neurotoxicity may include numbness, skin tingling, muscle twitching and convulsions. The risk of aminoglycoside-induced hearing loss increases with the degree of exposure to either high peak or high trough serum concentrations. Patients who develop cochlear damage may not have symptoms during therapy to warn them of eighth-nerve toxicity, and partial or total irreversible bilateral deafness may continue to develop after the drug has been discontinued. Rarely, nephrotoxicity may not become manifest until the first few days after cessation of therapy. Aminoglycoside-induced nephrotoxicity is usually reversible.
Therefore, renal and eighth cranial nerve function should be closely monitored in patients with known or suspected renal impairment and also in those whose renal function is initially normal but who develop signs of renal dysfunction during therapy. Evidence of impairment in renal, vestibular and/or auditory function requires discontinuation of the drug or dosage adjustment.
Monitoring of renal function is particularly important in elderly patients who may have reduced renal function that may not be evident in the results of routine screening tests, such as blood urea or serum creatinine. A creatinine clearance determination may be more useful.
Serum concentrations should be monitored when feasible, and prolonged concentrations above 12mg/l should be avoided. Rising trough levels (above 2mg/l) may indicate tissue accumulation. A useful guideline would be to perform serum level assays after two or three doses, so that the dosage could be adjusted if necessary, and also at three to four day intervals during therapy. In the event of changing renal function, more frequent serum levels should be obtained and the dosage or dosage intervals adjusted according to the guidelines provided in the 'Posology and Method of Administration' section. In order to measure the peak level, a serum sample should be drawn about 30 minutes following intravenous infusion or at one hour after intramuscular injection. Trough levels are measured by obtaining serum samples at eight hours or just prior to the next dose of tobramycin.
Urine should be examined for increased excretion of protein, cells and casts. Serum creatinine or creatinine clearance (preferred over blood urea) should be measured periodically. When feasible, it is recommended that serial audiograms be obtained in patients old enough to be tested, particularly high-risk patients.
The risk of toxic reactions is low in patients with normal renal function who do not receive tobramycin in higher doses or for longer periods of time than those recommended.
Patients with reduced renal function, however, are particularly prone to the potential ototoxic and nephrotoxic effects of this drug, so dosage should be adjusted carefully on the basis of regular monitoring of serum drug concentrations and of renal function.
Precautions
Use in neonates: Tobramycin should be used with caution in premature and neonatal infants because of their renal immaturity and the resulting prolongation of serum half-life of the drug.
General: Serum calcium, magnesium, and sodium should be monitored. It is particularly important to monitor serum levels closely in patients with known renal impairment.
In patients with extensive burns, altered pharmacokinetics may result in reduced serum concentrations of aminoglycosides. In such patients treated with tobramycin, measurement of serum concentration is especially recommended as a basis for determination of appropriate dosage.
Aminoglycosides may be absorbed in significant quantities from body surfaces after local irrigation or application and may cause neurotoxicity and nephrotoxicity.
Although not indicated for intraocular and/or subconjunctival use, there have been reports of macular necrosis following this type of injection.
Aminoglycosides should be used with caution in patients with muscular disorders, such as myasthenia gravis or parkinsonism, since these drugs may aggravate muscle weakness because of their potential curare-like effect on neuromuscular function.
Neuromuscular blockade or respiratory paralysis may occur following rapid intravenous administration of many aminoglycosides and have been reported in cats receiving very high doses of tobramycin (40mg/kg). The possibility of prolonged secondary apnoea should be considered if tobramycin is administered to anaesthetised patients who are also receiving neuromuscular blocking agents such as succinylcholine, tubocurarine or decamethonium, or to patients receiving massive transfusions of citrated blood. If neuromuscular blockade occurs, it may be reversed by the administration of calcium salts.
The inactivation of tobramycin by beta-lactam antibiotics (penicillins or cephalosporins) has been demonstrated in vitroand in patients with severe renal impairment. Such inactivation has not been found in patients with normal renal function if the drugs are administered by separate routes.
If overgrowth of non-susceptible organisms occurs, appropriate therapy should be initiated. Overdose
Toxicity may appear in patients who have been treated for more than 10 days, in adults who receive more than 5 mg/kg/day, in children who receive more than 7.5 mg/kg/day, or in patients with impaired renal function if the dose has not been appropriately adjusted. Similarly, elderly patients and patients treated with other nephrotoxic or ototoxic pharmaceutical preparations, or who are dehydrated, run a higher risk of developing acute tubular necrosis and ototoxicity.
The symptoms of tobramycin overdosing are:
Impaired hearing, dizziness, tinnitus, kidney damage.
In severe cases, neuromuscular blockade may occur. In addition, liver damage has also been reported.
In treating overdose, consideration must be given to the possibility that several medicinal products, as well as abnormal drug kinetics, may be involved.
Initially, the airway should be cleared and adequate supplies of oxygen and ventilation provided. In cases of respiratory paralysis, resuscitative treatment should begin immediately.
Patients who have a tobramycin overdose and who have normal renal function should be given appropriate fluids to maintain urine excretion at a rate of 3-5 ml/kg/hour. The fluid balance, creatinine clearance and tobramycin plasma levels should be carefully observed until the tobramycin plasma level has been reduced to less than 2 |ig/ml.
In patients with an elimination half-life of more than 2 hours or in patients with abnormal renal function, more aggressive therapy may be required. Dialysis may be beneficial for such patients.
Storage
Storage condition: This medicinal product does not require special storage conditions.
Chemical and physical in-use stability has been demonstrated in dextrose 5% w/v and sodium chloride 0.9% w/v infusion solutions for 48 hours at 25°C.
From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2-8° C, unless dilution has taken place in controlled and validated aseptic conditions.
For single use only. Discard any unused solution immediately after initial use.
Marketing Authorisation Holder
Mylan, Potters Bar, Hertfordshire, EN6 1TL, UK