What you need to know before you take it

such as amikacin, streptomycin, neomycin, in section 6). An allergic reaction may include Tobramycin Injection kanamycin, gentamicin or paromomcyin) rash, itching, difficulty breathing or swelling of 3. How you are given Tobramycin Injection  other antibiotics such as amphotericin B, the face, lips, throat or tongue. 4. Possible side effects cephaloridine, viomycin, polymyxin B, colistin, Tobramycin Injection must only be injected into vancomycin, and cephalosporin antibiotics (such 5. How to store Tobramycin Injection a muscle or vein. 6. Contents of the pack and other information as cephalothin) Warnings and precautions  cisplatin (a drug used for chemotherapy) 1 What Tobramycin Injection is and Tell your doctor if you:  diuretics (water tablets) what it is used for  Tobramycin Injection is a vial containing a solution have ever had an allergic reaction to a sulfate or  medicines used as muscle relaxants during general anaesthesia. bisulfite (preservatives) for injection of the active ingredient tobramycin,  ciclosporin (used to reduce the activity of the  have a kidney disorder or need dialysis which is an antibiotic. immune system) (you may need a reduced dose, especially if you Tobramycin Injection is used to treat the following  neostigmine and pyridostigmine (for the are elderly) infections caused by micro-organisms that can be  have a muscle disorder, such as myasthenia treatment of muscle weakness) killed by tobramycin:  warfarin and phenindione (used to thin gravis, or Parkinson's disease  blood poisoning the blood).  are elderly or dehydrated (needing fluids). Package leaflet: Information for the user

Tobramycin Injection 40 mg/ml





It may still be alright for you to be given Tobramycin Injection and your doctor will be able to decide what is suitable for you. Pregnancy, breast-feeding and fertility You should not have Tobramycin Injection if you are pregnant unless your doctor tells you to. Tobramycin may harm the unborn baby. You should not have Tobramycin Injection if you are breast-feeding. Ask your doctor or pharmacist for advice before taking any medicine. Driving and using machines Following rapid injection, Tobramycin Injection may cause muscle weakness or certain muscles not to work, and so may affect your ability to drive or use machines. If you are affected, you should not drive or operate heavy machinery until you feel it is safe to do so. Tobramycin Injection contains Sodium metabisulfite (E223) May rarely cause severe hypersensitivity reactions and bronchospasm (difficulty in breathing). Information about Sodium content This medicine contains less than 1 mmol sodium (23 mg) per ml, that is to say essentially 'sodium free'.

How to take it

Tobramycin Injection

Dosage A doctor or nurse will give you Tobramycin Injection.

INFORMATION FOR THE HEALTH CARE PROFESSIONAL

Table 1: DOSAGE SCHEDULE GUIDE FOR ADULTS WITH NORMAL RENAL FUNCTION (Dosage at 8 Hour Intervals)

1. NAME OF THE MEDICINAL PRODUCT

Patient Usual dose for serious Maximum dose for life threatening Weight infections 1mg/kg q 8 h infections (reduce as soon as possible) kg (total 3mg/kg/day) 1.66mg/kg q 8 h (total 5mg/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

Tobramycin Injection 40mg/1ml 4. CLINICAL PARTICULARS 4.1 Therapeutic Indications Consideration should be given to official guidance on the appropriate use of antibacterial agents. Tobramycin Injection is indicated for the treatment of the following infections caused by susceptible micro organisms: Central nervous system infections, including meningitis, septicaemia and neonatal sepsis Gastro-intestinal infections, including peritonitis, and other significant infections such as complicated and recurrent urinary tract infections, including pyelonephritis and cystitis Lower respiratory tract infections, including pneumonia, bronchopneumonia and acute bronchitis Skin, bone and soft tissue infections, including burns 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. See section 5.1. for species clinical breakpoints and prevalence of resistance of commonly susceptible bacterial species. 4.2 Posology and method of administration Posology 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 3mg/kg/day, administered in three equal doses every eight hours (Table 1). For life threatening infections, dosages up to 5mg/kg/day may be administered in three or four equal doses. The dosage should be reduced to 3mg/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 10mg/kg/day in equally divided doses. Because serum concentrations of tobramycin vary from one patient to another, serum levels should be monitored.

*Applicable to 40mg/ml product forms. In adults with normal renal function, mild to moderate infections of the urinary tract have responded to a dosage of 2-3mg/kg/day administered as a single intramuscular injection. The elderly: As for adults, but see recommendations for patients with impaired renal function. 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. Paediatric population Children: The recommended dosage is 6-7.5mg/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 4mg/kg/day may be administered in two equal doses every 12 hours, for those between 1.5 and 2.5kg 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. Patients with impaired renal function Following a loading dose of 1mg/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

4.3 Contraindications Intrathecal administration. Hypersensitivity to any aminoglycoside is a contra-indication to the use of tobramycin because of the known cross-allergenicity of drugs in this class. 4.4 Special warnings and precautions for use Warnings Tobramycin Injection contains sodium metabisulfite which may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes, in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low, but it occurs more frequently in asthmatic patients. Regimen II Patients treated with tobramycin should be Renal function† Regimen I

under close observation because tobramycin and

Adjusted doses at Normal dosage other aminoglycoside antibiotics have an

8 hour intervals at prolonged inherent potential for causing nephrotoxicity intervals

and ototoxicity. Patients with mitochondrial DNA Blood urea Serum creatinine Creatinine Weight Weight/Dose mutations, particularly the nucleotide 1555 A to clearance

G substitution in the 12S rRNA gene may be at 50-60kg: 60mg higher risk for ototoxicity, even if the patient's mg/100ml mmol/l mg/100ml mcmol/l ml/min 50-60kg 60-80kg

60-80kg: 80mg aminoglycoside serum levels were within the

recommended range. In case of family history of Normal: aminoglycoside-induced deafness or known <42 <7.0 <1.3 <114.9 >70 60mg 80mg q 8 h q 12 h mitochondrial DNA mutations in the 12S rRNA 42-74 7.0-12.3 1.4-1.9 123.8-168 69-40 30-60mg 50-80mg q 18 h gene, alternative treatments other than 75-105 12.5-17.5 2.0-3.3 176.8-291.7 39-20 20-25mg 30-45mg

aminoglycosides may need to be considered. 106-140 17.7-23.3 3.4-5.3 300.6-468.5 19-10 10-18mg 15-24mg q 24 h q 36 h Both vestibular and auditory ototoxicity can 141-160 23.5-26.7 5.4-7.5 477.4-663 9-5 5-9mg 7-12mg q 48 h§ occur. The auditory changes are irreversible, are >160 >26.7 >7.6 >671.8 <4 2.5-4.5mg 3.5-6mg

usually bilateral, and may be partial or total.

• For life threatening infections, dosages 50% above those Eighth cranial nerve impairment may develop in patients with normally recommended may be used. The dosages should be pre-existing renal damage and if tobramycin is administered for longer reduced as soon as possible when improvement is noted. periods or in higher doses than those recommended. Other † If used to estimate degree of renal impairment, blood urea and manifestations of neurotoxicity may include numbness, skin tingling, serum creatinine concentrations should reflect a steady state of muscle twitching and convulsions. The risk of aminoglycoside-induced renal uraemia. hearing loss increases with the degree of exposure to either high peak § When dialysis is not being performed. or high trough serum concentrations. Patients who develop cochlear Following IM administration of a single dose of tobramycin of l mg/kg damage may not have symptoms during therapy to warn them of in adults with normal renal function, peak plasma tobramycin eighth nerve toxicity, and partial or total irreversible bilateral deafness concentrations averaging 4-6 micrograms/ml are attained within may continue to develop after the drug has been discontinued. 30-90 minutes; plasma concentrations of the drug are 1 microgram/ml Rarely, nephrotoxicity may not become manifest until the first few or less at 8 hours. Following intravenous infusion of the same dose over days after cessation of therapy. Aminoglycoside-induced 30-60 minutes, similar plasma concentrations of the drug are obtained. nephrotoxicity is usually reversible. In neonates, average peak plasma tobramycin concentrations of about Therefore, renal and eighth cranial nerve function should be closely 5 micrograms/ml are attained 30-60 minutes after a single IM dose of monitored in patients with known or suspected renal impairment and 2mg/kg; plasma concentrations average 1-2 micrograms/ml at 12 hours. also in those whose renal function is initially normal but who develop signs of renal dysfunction during therapy. Evidence of impairment in Method of administration renal, vestibular and/or auditory function requires discontinuation of Tobramycin may be given intramuscularly or intravenously. The patient's pre-treatment body weight should be obtained for calculation the drug or dosage adjustment. Monitoring of renal function is particularly important in elderly patients of correct dosage. who may have reduced renal function that may not be evident in the For instructions on dilution of the medicinal product before results of routine screening tests, such as blood urea or serum administration, see section 6.6. 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 1mg/kg*

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 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. May rarely cause severe hypersensitivity reactions and bronchospasm. This medicinal product contains less than 1 mmol sodium (23 mg) per ml, that is to say essentially 'sodium-free'. Paediatric population 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. 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 Pregnancy Aminoglycosides can cause foetal harm when administered to a pregnant woman. Aminoglycoside antibiotics cross the placenta, and there have been several reports of total irreversible bilateral congenital deafness in children whose mothers received streptomycin during pregnancy. Serious side-effects to mother, foetus, or newborn have not been reported in the treatment of pregnant women with other aminoglycosides, but tobramycin should not be administered to the pregnant patient unless the potential

benefits clearly outweigh any potential risk. If tobramycin is used during pregnancy or if the patient becomes pregnant whilst taking tobramycin, she should be informed of the potential hazard to the foetus. Breast-feeding Tobramycin is excreted in the breast milk and should be avoided in nursing women. 4.7 Effects on ability to drive and use machines Not relevant 4.8 Undesirable effects Renal function changes, as shown by rising blood urea and serum creatinine and by oliguria, cylindruria and increased proteinuria, have been reported, especially in patients with a history of renal impairment who are treated for longer periods or with higher doses than those recommended. These changes can occur in patients with initially normal renal function. Side-effects on both vestibular and auditory branches of the eighth cranial nerve have been reported, especially in patients receiving high doses or prolonged therapy, in those given previous courses of therapy with an ototoxin, and in cases of dehydration. Symptoms include dizziness, vertigo, tinnitus, roaring in the ears and hearing loss. Hearing loss is usually irreversible and is manifested initially by diminution of high tone acuity. Other reported side effects, possibly related to tobramycin, include increased AST, ALT and serum bilirubin; decreased serum calcium, magnesium, sodium and potassium; anaemia, granulocytopenia, thrombocytopenia, leucopenia, leucocytosis and eosinophilia; and fever, rash, exfoliative dermatitis, itching, urticaria, nausea, vomiting, diarrhoea, headache, lethargy, pain at the injection site, mental confusion and disorientation. Reporting of suspected adverse reactions Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continues 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 Website: www.mhra.gov.uk/yellowcard. 4.9 Overdose Signs and Symptoms: Severity of the manifestations of a tobramycin overdose depend on the dose, the patient's renal function, state of hydration, age and whether concurrent medication with similar toxicities is being given. Toxicity may occur in patients treated for more than 10 days, given more than 5mg/kg/day, children given more than 7.5mg/kg/day, or patients with reduced renal function whose dose has not been appropriately adjusted. Nephrotoxicity following the parenteral administration of an aminoglycoside is most closely related to the AUC of serum concentration versus time. Nephrotoxicity is more likely if trough levels fail to fall below 2mg/l and is also proportional to the average blood concentration. Patients who are elderly, have renal impairment, are receiving other nephrotoxic or ototoxic drugs, or are volume depleted, are at greater risk for developing acute tubular necrosis. Auditory and

vestibular toxicities have been associated with aminoglycoside overdose. These toxicities occur in patients treated longer than 10 days, in patients with abnormal renal function, in dehydrated patients, or in patients on other ototoxic drugs. These patients may not have signs or symptoms, or may experience dizziness, tinnitus, vertigo and a loss of high tone acuity. Signs and symptoms may not occur until long after the drug has been discontinued. Neuromuscular blockade or respiratory failure may occur following rapid intravenous administration of many aminoglycosides. These reactions and prolonged respiratory paralysis may occur more commonly in patients with myasthenia gravis or Parkinson's disease, or those receiving decamethonium, tubocurarine or succinylcholine. Neuromuscular blockade may be reversed by the administration of calcium salts, but mechanical assistance may be necessary. Toxicity from ingested tobramycin is unlikely because aminoglycosides are poorly absorbed from an intact gastro-intestinal tract. Treatment: Resuscitative measures should be initiated promptly if respiratory paralysis occurs. Neuromuscular blockade may be reversed by giving calcium salts. Fluid balance, creatinine clearance and tobramycin plasma levels should be carefully monitored until the tobramycin level falls below 2mg/l. Haemodialysis or peritoneal dialysis will help remove tobramycin from the blood. Between 25% and 70% of the administered dose may be removed, depending on the duration and type of dialysis employed; haemodialysis is the more effective method. 5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Aminoglycoside antibacterials, ATC code: JO1GB01 Mode of Action: in vitro tests demonstrate that tobramycin is bactericidal and that it acts by inhibiting the synthesis of protein in bacterial cells. 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

5.2 Pharmacokinetic properties The serum half-life in normal individuals is two hours. An inverse Gram-negative aerobes relationship exists between serum half-life and creatinine clearance, Citrobacter freundii and the dosage schedule should be adjusted according to the degree Citrobacter koseri of renal impairment (see 'Posology and Method of Administration'). Enterobacter aerogenes In patients undergoing dialysis, 25% to 70% of the administered Enterobacter cloacae dose may be removed, depending on the duration and type of Enterobacter sakazakii dialysis. Enterobacter spp Tobramycin can be detected in tissues and body fluids after parenteral administration. Concentrations in bile and stools ordinarily Escherihia coli

Klebsiella oxytoca have been low, which suggests minimum biliary excretion. Tobramycin has appeared in low concentration in the cerebrospinal

Klebsiella pneumoniae fluid following parenteral administration and concentrations are

Klebsiella spp dependent on dose, rate of penetration and degree of meningeal

Morganella morganii inflammation. It has also been found in sputum, peritoneal fluid,

Proteus mirabilis synovial fluid and abscess fluids, and it crosses the placental

Proteus spp membranes. Concentrations in the renal cortex are several times

Proteus vulgaris higher than the usual serum levels. Tobramycin levels may be somewhat lower than expected in adults

Pseudomonas aeruginosa with a large volume of extracellular fluid. Also, it has been reported Species for which acquired resistance may be a problem that the serum half-life of tobramycin in severely burned patients Gram-positive aerobes Gram-negative aerobes may be decreased and this may result in lower serum levels. Staphylococcus capitis Citrobacter spp – other Probenecid does not affect the renal tubular transport of tobramycin. Staphylococcus epidermidis Klebsiella ozaenae 5.3 Preclinical safety data Staphylococcus haemolyticus Serratia liquefaciens There are no preclinical data of relevance to the prescriber. Staphylococcus hominis Serratia marcescens 6. PHARMACEUTICAL PARTICULARS Staphylococcus lugdunensis Serratia spp 6.6 Special precautions for disposal and other handling Staphylococcus warnerii Prior to administration, parenteral drug products should be inspected Inherently resistant organisms visually for particulate matter and discolouration whenever solution Aminoglycosides have a low order of activity against most and container permit. gram-positive organisms, including Streptococcus pyogenes, Intramuscular administration: Tobramycin Injection may be Streptococcus pneumoniae and enterococci. administered by withdrawing the appropriate dose directly from Although most strains of enterococci demonstrate in vitro resistance, the vial. some strains are susceptible. In vitro studies have shown that an Intravenous administration: For intravenous administration, the aminoglycoside combined with an antibiotic that interferes with usual volume of diluent (0.9% Sodium Chloride Intravenous Infusion cell-wall synthesis affects some enterococcal strains synergistically. The BP or 5% Dextrose Intravenous Infusion BP) for adult doses is combination of penicillin G and tobramycin results in a synergistic 50-100ml. For children, the volume of diluent should be bactericidal effect in vitro against certain strains of Enterococcus proportionately less than for adults. The diluted solution should be faecalis (formerly Streptococcus faecalis). infused over a period of 20-60 minutes avoiding admixture with any However, this combination is not synergistic against other closely other drug. Tobramycin Injection may be administered slowly by related organisms, e.g. Enterococcus faecium (formerly Streptococcus direct intravenous injection or into the tubing of a drip set. When faecium). Speciation of enterococci alone cannot be used to predict given in this way, serum levels may exceed 12mg/l for a short time susceptibility. Susceptibility testing and tests for antibiotic synergism (see 'Contra indications, Warnings, etc.'). are emphasised. No special requirements for disposal. Cross resistance between aminoglycosides occurs and depends largely Any unused medicinal product or waste on inactivation by bacterial enzymes. material should be disposed of in accordance The combination of tobramycin and carbenicillin is synergistic in vitro with local requirements against most strains of Ps. aeruginosa. Other Gram-negative organisms 10. DATE OF REVISION OF THE TEXT may be affected synergistically by the combination of tobramycin and July 2021 a cephalosporin.

The recommended dose is: Adults: 3mg per kg of body weight every 24 hours, given as 3 doses of 1mg per kg of body weight every 8 hours. If you have a serious bacterial infection, your doctor may use larger doses. Use in children and adolescents Children: 6 to 7.5mg per kg of body weight every 24 hours, given as 3 or 4 equal doses. Premature or new-born babies: Up to 4mg per kg of body weight every 24 hours, given as 2 equal doses every 12 hours. Kidney disorder: 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 have any further questions on the use of this medicine, ask your doctor or pharmacist.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them. Very serious side effects All medicines can cause allergic reactions, although serious allergic reactions are very rare. Tell your doctor straight away if you get any sudden wheeziness, difficulty in breathing, swelling of the eyelids, face or lips, rash or itching (especially affecting your whole body), or any of the following:

severe peeling skin (exfoliative dermatitis) ringing or roaring in one or both ears (tinnitus)  hearing loss in one or both ears  dizziness  sensation of spinning (vertigo)  muscle twitching  numbness or pins and needles  fits  changes in the number of different types of blood cells. You may notice unexplained bleeding or bruising (caused by low platelets) or are unable to fight off infections (reduced levels of white blood cells), feel tired all the time (reduced blood cells, anaemia) or have sudden fever or sore throat.* These are serious side effects, and you may only notice them after you stop treatment. You should see your doctor immediately. The following side effects have also been reported:  effects on the kidneys causing an increase in waste products in the blood which are normally eliminated by them or the kidneys not to work properly  reduced or no urine production  cloudy urine (caused by protein or granules). If you notice changes in your urine or the number of times you need to urinate, tell your doctor straight away. Other side effects reported are:  headache  tiredness  confusion and disorientation

fever rash (with no other symptoms)  itching  feeling sick  being sick  diarrhoea  pain at the injection site  raised liver enzymes*  the amount of calcium, magnesium, sodium and potassium in your blood may decrease (symptoms are muscle weakness, muscle cramps, feeling thirsty all the time, drinking all the time, urinating frequently, vomiting and, possibly, having a fit)* *(these conditions would be detected in a blood test carried out by a doctor). Reporting of side effects If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store. By reporting side effects you can help provide more information on the safety of this medicine.









How to store it

Tobramycin Injection

Your doctor or pharmacist knows how to store Tobramycin Injection. Keep this medicine out of the sight and reach of children. Store below 25°C.

Do not use this medicine after the expiry date which is stated on the carton. The expiry date refers to the last day of that month. Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use.These measures will help protect the environment.

Contents of the pack and other information

What Tobramycin Injection contains Each 1ml solution contains 40mg of the active substance tobramycin. The other ingredients are: phenol, sodium metabisulfite, disodium edetate, water for injection, sulfuric acid. What Tobramycin Injection looks like and contents of the pack Tobramycin Injection is a clear, colourless solution provided in rubber stoppered glass vials in individual cartons. Marketing Authorisation Holder Flynn Pharma Ltd 5th Floor, 40 Mespil Road Dublin 4, IRELAND, D04 C2N4 Manufacturer Vianex SA 12th km National Road Athens-Lamia, 14451 Metamorphossis Attiki Athens, Greece. This leaflet was last revised in May 2022.

Artwork for: Product name: PL/PA no: Type: Artwork dimensions: Profile supplied: Date of first artwork: Reason for request: Version no: Date of revision: Colours: Font(s): Artwork software: Proof software: BAC ref:

Flynn Pharma Limited Tobramycin Injection PL 13621/0059 Leaflet 115mm x 530mm No. Estimated 11 March 2019 MAH address change 11FP 6 May 2022 As swatch(es) 8pt FF Zwo equivalent to 9pt Times New Roman InDesign CS6 PDF Z459 (formerly Y431)

Black