SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Tobramycin 40 mg/ml Solution for Injection or Infusion

2    QUALITATIVE AND QUANTITATIVE    COMPOSITION

Each ml of solution contains 40 mg tobramycin (as tobramycin sulfate).

Excipient: less than 22mg (0.0625 mmol) of sodium (as bisulphite) per vial.

For the full list of excipients, see section. 6.1.

3    PHARMACEUTICAL FORM

Solution for Injection or Infusion.

Clear and colorless solution.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Tobramycin injection is indicated for the treatment of the    following infections caused

by susceptible micro-organisms (see section 5.1):

•    Acute bacterial meningitis (see section 4.4)

•    Peritonitis

•    Complicated and recurrent urinary tract infections, including pyelonephritis and cystitis

•    Nosocomial lower respiratory tract infections, including severe pneumonia

•    Skin, soft tissues infections including burns

Consideration should be given to official guidance on the appropriate use of antibacterial agents.

Tobramycin injection may be considered in serious staphylococcal infections for which penicillin or other less potentially toxic drugs are contra-indicated and when bacterial susceptibility testing and clinical judgement indicate its use.

4.2 Posology and method of administration

Tobramycin injection may be given intramuscularly or intravenously. The patient's pre-treatment body weight should be obtained for calculation of correct dosage.

For instructions on dilution of the product before administration see section 6.6.

The intramuscular dose is the same as the intravenous dose.

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	Usual dose for serious	Maximum dose for life-
Weight kg	infections 1 mg/kg q 8 h (total 3 mg/kg/day)	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.

Special caution is recommended for treatment of premature and neonates. Dosage should be individualized based on severity of disease, renal function, susceptibility of bacterial isolates. Serum concentration should be monitored.

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.

|If 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.

4.3 Contraindications

Hypersensitivity to tobramycin, other aminoglycosides or to one or more of the excipients.

4.4 Special warnings and precautions for use

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, i.e. 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.

In treatment of acute bacterial meningitis caused by Psuedominas aeruginosa, Tobramycin may be used in combination with other appropriate antibacterial agents.

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 halflife 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 vitro and 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.

4.5 Interaction with other medicinal products and other forms of interaction

Concurrent and/or sequential use of other potentially neurotoxic and/or nephrotoxic drugs, particularly other aminoglycosides (eg, amikacin, streptomycin, neomycin, kanamycin, gentamicin and paromomycin), amphotericin B, cephaloridine, viomycin, polymyxin B, colistin, cisplatin and vancomycin, requires careful monitoring. Other factors that may increase patient risk are advanced age and dehydration.

Tobramycin should not be given concurrently with potent diuretics. Some diuretics themselves cause ototoxicity, and intravenously administered diuretics enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue.

Antibacterials: Tobramycin used in conjunction with other antibacterials such as cephalosporins notably cephalothin, there is an increased risk of nephrotoxicity.

Muscle Relaxants: Enhanced blockade of respiratory paralysis can occur with skeletal muscle relaxants.

Cytotoxics and Cyclosporins: There is increased risk of nephrotoxicity and possibly ototoxicity with Cisplatin as well as increased risk of nephrotoxicity with cyclosporins.

Tobramycin has been known to potentiate warfarin and phenindione.

Cholinergics: Antagonism of effect of neostigmine and pyridostigmine.

4.6 Fertility, Pregnancy and lactation

Fertility:

The effect of tobramycin on fertility is unknown. Pregnancy:

Animal studies do not indicate a teratogenic effect of tobramycin (see section 5.3). However, aminoglycosides cross the placenta and may cause fetal injury (e.g. congenital deafness) when used in pregnant women.

If tobramycin is used during pregnancy, or if the patient is pregnant during tobramycin therapy, the woman should be informed about the potential risk to the foetus.

Lactation:

Studies in breast-feeding women indicate that small amounts of tobramycin are excreted in breast milk. Due to the potential for serious adverse reactions, a decision must be made whether to discontinue breast-feeding or to discontinue/abstain from treatment with Tobramycin.

4.7 Effects on ability to drive and use machines

Tobramycin has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

Blood and lymphatic system disorders
Common - very common (> 1 / 100) Rare - very rare (<1 / 1000)	Eosinophilia. Anemia, granulocytopenia, leukopenia, thrombocytopenia.
Metabolic and nutritional disorders
Rare - very rare (<1 / 1000)	Decreased serum calcium, magnesium, Sodium and potassium.
Disorders of the central and peripheral nervous system
Uncommon (> 1 / 1000 and <1 / 100) Rare - very rare (<1 / 1000) Unknown frequency	Headache. Mental confusion, disorientation. Numbness, prickly sensation in the skin.
Ear and labyrinth disorders
Common - very common (> 1 / 100)	Hearing loss, dizziness, vertigo, tinnitus in patie with renal impairment.
Uncommon (> 1 / 1000 and <1 / 100)	Hearing loss, dizziness, vertigo, tinnitus in patie with normal renal function.
Vascular (extracardial) disorders
Common - very common (> 1 / 100)	Thrombophlebitis.

Gastrointestinal disorders
Uncommon (> 1 / 1000 and <1 / 100) Rare - very rare (<1 / 1000)	Vomiting, discomfort. Diarrhoea.
Liver and biliary disorders
Common - very common (> 1 / 100) Uncommon (> 1 / 1000 and <1 / 100)	Increase of transaminases. Increase of alkaline phosphatase, LD and bilirubin.
Skin and subcutaneous tissue disorders Uncommon (> 1 / 1000 and <1 / 100) Very rare (<1/10.000, including isolated cases)	Exanthema, urticaria, pruritus. Stevens-Johnson syndrome, toxic epiderma necrolysis.
Muskuloskeletal, connective tissue and bone disorders Unknown frequency	Twitching muscles, spasms.
Renal and urinary disorders Common - very common (> 1 / 100)	Renal function changes in patients with rei

Uncommon (> 1 / 1000 and <1 / 100)	impairment. Renal function changes in patients with normal renal function.
General disorders and administration site conditions Common - very common (> 1 / 100) Rare - very rare (<1 / 1000)	Pain and local reactions at the injection sit< Fever, lethargy.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms

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.

Management

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 gg/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.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Antibacterials for systemic use, other aminoglycosides; ATC code: J01GB01

Mechanism of action

Tobramycin is an aminoglycoside antibiotic derived from nebramycin, an antibiotic complex of eight chemically related compounds produced by Streptomyces tenebrarius. Tobramycin inhibits protein synthesis through an interaction with the 30S ribosomal subunit. The binding of tobramycin to the subunit is permanent; that subunit is removed from the polysome pool, and thus protein synthesis is inhibited in a bactericidal manner. Although misreading of polypeptide synthesis occurs in vitro, the major in vivo action of tobramycin and other aminoglycosides is probably related to depletion of the ribosome pool. Tobramycin is much more active against Pseudomonas aeruginosa and is also active in vitro against other major gramnegative pathogens, such as Escherichia coli, the Klebsiella-Enterobacter-Serratia group, Proteus species (indole-positive and indole-negative), Providencia species, and Citro-bacter species. Cross-resistance between tobramycin and gentamicin is generally seen, but about 10% of strains resistant to gentamicin are susceptible to tobramycin.

EUCAST Clinical MIC Breakpoints

The non-species related breakpoints for susceptible (S) and resistant (R) species are: S < 2mg/L and R > 4mg/L

For Enterobacteriacaea	S<2mg/L and R>4mg/L
For Pseudomonas	S<4mg/L and R>4mg/L
For Acinetobacter	S<4mg/L and R>4mg/L
For Staphylococcus	S<1mg/L and R>1mg/L

The prevalence of acquired resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in at least some types of infections is questionable.

Commonly Susceptible Species
Gram-positive aerobes	Staphylococcus aureus Staphylococcus coagulase negative Staphylococcus saprophyticus

Gram-negative aerobes	Citrobacter freundii Citrobacter koseri Enterobacter aerogenes Enterobacter cloacae Enterobacter sakazakii Enterobacter spp Escherichia coli Klebsiella oxytoca Klebsiella pneumonia Klebsiella spp Morganella morganii Proteus mirabilis Proteus spp Proteus vulgaris Pseudomonas aeruginosa
Species for which acquired resistance may be a problem
Gram-positive aerobes	Staphylococcus capitis Staphylococcus epidermidis
	Staphylococcus haemolyticus Staphylococcus hominis Staphylococcus lugdunensis Staphylococcus warnerii
Gram-negative aerobes	Citrobacter spp-other Klebsiella ozaenae Serratia liquefaciens Serratia marcescens Serratia spp

Inherently resistant organisms

Aminoglycosides have a low order of activity against most gram-positive organisms, including Streptococcus pyogenes, Streptococcus pneumoniae and enterococci.

Although most strains of enterococci demonstrate in vitro resistance, some strains are susceptible. In vitro studies have shown that an aminoglycoside combined with an antibiotic that interferes with cell-wall synthesis affects some enterococcal strains synergistically.

The combination of penicillin G and tobramycin results in a synergistic bactericidal effect in vitro against certain strains of Enterococcus faecalis (formerly Streptococcus faecalis).

However, this combination is not synergistic against other closely related organisms, e.g. Enterococcus faecium (formerly Streptococcus faecium). Speciation of enterococci alone cannot be used to predict susceptibility. Susceptibility testing and tests for antibiotic synergism are emphasised.

Cross-resistance between aminoglycosides occurs and depends largely on inactivation by bacterial enzymes.

The combination of tobramycin and carbenicillin is synergistic in vitro against most strains of Ps. aeruginosa. Other Gram-negative organisms may be affected synergistically by the combination of tobramycin and a cephalosporin.

5.2 Pharmacokinetic properties

Absorption

Tobramycin sulphate is poorly absorbed from the gastrointestinal tract, but is rapidly absorbed following intramuscular administration.

Distribution

Maximum plasma concentration of tobramycin is reached after 30 to 90 minutes following intramuscular administration.

Following intramuscular injection of a dose of 1 mg/kg body weight, maximum plasma concentrations of approximately 4 pg/ml have been observed and measurable plasma levels can be observed for up to 8 hours. The therapeutic plasma concentration is generally considered to be 4-6 pg/ml. When tobramycin is administered as an intravenous infusion over one hour, the same plasma concentration can be reached as with intramuscular administration. Following an intravenous bolus injection of a single dose of 1.5 mg/kg maximum plasma concentration is rapidly achieved at values between 9.2 to 29.8 pg/ml. This concentration falls to less than 11 pg/ml within 15 minutes.

In patients with normal renal function, except newborns, tobramycin administered every 8 hours does not accumulate in plasma. In contrast, in patients with impaired renal function and in newborns, the tobramycin plasma concentration is higher and can be measured for a longer time than in adults with normal renal function.

Metabolism and Elimination

Following parenteral administration of tobramycin, only a minor fraction is metabolised, and tobramycin is almost exclusively eliminated by glomerular filtration. Plasma protein binding is virtually non-existent. In patients with normal renal function, up to 93% of the dose can be recovered in urine over 24 hours.

Maximum urine concentrations with values between 75 to 100 pg/ml have been observed following intramuscular injection of a single 1 mg/kg dose. After several days of treatment, the amount of tobramycin excreted in urine approaches the injected daily dose. Excretion of tobramycin is reduced in the case of impaired renal function, and accumulation of the drug may cause toxic blood levels.

The plasma half-life in normal persons is 2 hours. Due to the inverse relationship between plasma half-life and creatine clearance, the dosage regimen should be adjusted to the degree of renal impairment. In patients undergoing dialysis, 25 to 70% percent of the administered dose is lost depending on the type of dialysis.

Preclinical safety data

Pre clinical data reveal that the main hazards for humans, based on safety pharmacology, repeated dose toxicity, genotoxicity or reproductive toxicity, are nephrotoxicity and ototoxicity. In repeat dose studies, toxicity is targeted at the kidneys and vestibular/cochlear functions.

Subcutaneous administration of tobramycin 100 mg/kg/day in rats and the maximum tolerated dose of 20 mg/kg/day in rabbits, during organogenesis, was not teratogenic. Teratogenicity could not be assessed at higher parenteral doses in rabbits due to maternal toxicity and abortion. Based on available data from animals, a risk of toxicity (e.g. ototoxicity) at pre natal exposures cannot be excluded.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Disodium edetate Sodium bisulfite (E222)

Sulfuric acid (for pH-adjustment) Sodium hydroxide (for pH-adjustment) Water for Injections.

6.2 Incompatibilities

This medicine should not be mixed with other medicinal products except those mentioned in section. 6.6.

6.3 Shelf life

Shelf life of unopened vial: 2 years.

In use:

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.

6.4 Special precautions for storage

This product does not require any special storage conditions

For storage conditions after dilution of the medicinal product, see section 6.3

6.5 Nature and contents of container

10 vials x 2 ml

Type I tubular flint moulded vial with bromo butyl dark grey rubber stopper and flip off aluminium seal.

6.6 Special precautions for disposal

When administered by intravenous infusion an adult dose of tobramycin may first 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.

The volume of diluent for a child's dose should be proportionally less than that for an adult dose.

For single use only. Discard any unused solution immediately after initial use.

7    MARKETING AUTHORISATION HOLDER

Generics [UK] Limited t/a Mylan

Station Close

Potters Bar

Hertfordshire

EN6 1TL

United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 04569/1549

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

28/04/2014

10    DATE OF REVISION OF THE TEXT

13/11/2014