Summary of medicine characteristics - TOBRAMYCIN 40 MG / ML SOLUTION FOR INJECTION
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
Because of the known cross-allergenicity of drugs in this class, hypersensitivity to any aminoglycoside is a contraindication to the use of tobramycin.
4.4.
Special warnings and precautions for use
Tobramycin injection contains sodium metabisulphite 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 sulphite sensitivity in the general population is unknown and probably low, but it occurs more frequently in asthmatic patients.
Cross-allergenicity among aminoglycosides has been known to occur. Patients treated with aminoglycoside antibiotics such as tobramycin should be under close clinical observation because these drugs have an inherent potential for causing nephrotoxicity and ototoxicity.
Both vestibular and auditory ototoxicity can occur. Eighth 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 with mitochondrial DNA mutations, particularly the nucleotide 1555 A to G substitution in the 12S rRNA gene may be at higher risk for ototoxicity, even if the patient’s aminoglycoside serum levels were within the recommended range. In case of family history of aminoglycoside-induced deafness or known mitochondrial DNA mutations in the 12S rRNA gene, alternative treatments other than aminoglycosides may need to be considered.
Patients who develop cochlear damage may not have symptoms during therapy to warn of eighthnerve 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.
In elderly patients, it is particularly important to monitor renal function, when reduced renal function 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 possible, and prolonged concentrations above 12 mg/litre should be avoided. A useful guideline would be to perform serum level assays after 2 or 3 doses and also at 3 or 4 day intervals during therapy, so that the dosage could be adjusted if necessary. 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 (see section 4.2). 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 8 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 possible, it is recommended that serial audiograms be obtained in patients old enough to be tested, particularly high-risk patients.
In patients with normal renal function who do not receive tobramycin in higher doses or for longer periods of time than those recommended, the risk of toxic reactions is low.
However, patients with reduced renal function are 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.
Concurrent and sequential use of other nephrotic, neurotoxic or ototoxic drugs, particularly streptomycin, neomycin, kanamycin, gentamicin, cephaloridine, paromomycin, viomycin, polymyxin B, colistin, cisplatin, vancomycin and amikacin, should be avoided. Advanced age and dehydration may also increase patient risk.
Tobramycin should not be given concurrently with potent diuretics. Some diuretics themselves cause ototoxicity, and diuretics administered intravenously enhance aminoglycoside toxicity by altering antibiotic concentrations in serum and tissue.
4.4 Interaction with other medicinal products and other forms of interaction
4.4 Interaction with other medicinal products and other forms of interactionAntibacterials: Tobramycin used in conjunction with other antibacterials such as cephalosporins notably cephalothin, there is an increased risk of nephrotoxicity.
Antifungals: Amphotericin B may produce synergistic renal toxicity.
Diuretics: Tobramycin should not be given in conjunction with ethacrynic acid, furosemide or other potent diuretics which may cause ototoxicity or enhance aminoglycoside toxicity.
General anaesthetics and Neuromuscular Blocking Agents: Concurrent use of tobramycin with general anaesthetics (e.g. succinylcholine, tubocurarine) may potentiate neuromuscular blockade and cause respiratory paralysis.
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
4.6 Fertility, pregnancy and lactationPregnancy
Aminoglycoside antibiotics cross the placenta and can cause foetal harm when administered to a pregnant woman. Serious side effects to mother, foetus or newborn have been reported in the treatment of pregnant women with aminoglycosides (e.g., several reports of total irreversible bilateral congenital deafness in children whose mothers received streptomycin during pregnancy).
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.
4.5 Effects on ability to drive and use machines
4.5 Effects on ability to drive and use machinesNot relevant.
4.8 Undesirable effects
4.8 Undesirable effectsRenal and urinary disorders:
Renal function changes such as 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 these recommended. These changes can occur in patients with initially normal renal function.
In patients receiving high doses or prolonged therapy, side effects on both vestibular and auditory branches of the eighth cranial nerve have been reported. Similar effects have been noted in those given previous courses of therapy with an ototoxin, and in cases of dehydration. Symptoms include vertigo, tinnitus, roaring in the ears and hearing loss. Hearing loss is usually irreversible and is manifested initially by diminution of high tone acuity.
Dizziness, headache, lethargy.
Increased AST, ALT, and serum bilirubin; decreased serum calcium, magnesium, sodium, potassium.
Anaemia, granulocytopenia, thrombocytopenia, leucopenia, leucocytosis and eosinophilia.
Immune system disorders
Hypersensitivity.
Fever, pain at injection site.
Rash, itching, urticaria, exfoliative dermatitis.
Nausea, vomiting, diarrhea.
Mental confusion and disorientation.
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 or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 Overdose
4.9 OverdoseSeverity 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 concentrations versus time. Nephrotoxicity is more likely if trough levels fail to fall below 2 micrograms/ml 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 or auditory and vestibular toxicity. 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 often experience dizziness, tinnitus, vertigo and a loss of high-tone acuity. 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.
Toxicity from ingested tobramycin is unlikely because aminoglycosides are poorly absorbed from an intact gastro-intestinal tract.
Treatment of Overdose:
Resuscitative measures should be initiated promptly if respiratory paralysis occurs. Haemodialysis or peritoneal dialysis will help remove tobramycin from the blood in the event of overdosage or toxic reactions. Depending on the duration and type of dialysis employed, approximately 25–70% of the administered dose may be removed. Haemodialysis is the more effective method. Fluid balance, creatinine clearance and tobramycin plasma levels should be carefully monitored until the tobramycin level falls below 2mg/l. Calcium salts given intravenously have been used to counter neuromuscular blockade, the effectiveness of neostigmine has been variable.
5 pharmacological properties
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Aminoglycoside Antibacterials, ATC Code: J01G B01
Mechanism of action
Tobramycin is bactericidal in activity. It enters the cells via complex active transport mechanism and exerts its activity primarily on the 30S ribosomal subunit, interfering with initial and subsequent steps in protein synthesis. It also acts to induce misreading of the genetic code of the mRNA template, resulting in incorporation of incorrect amino acids.
Tobramycin, in common with all other aminoglycosides, is primarily antibacterial against aerobic Gram-negative bacilli. Tobramycin is considered more active than most other aminoglycosides against Pseudomonas aeruginosa.
Tobramycin is usually active against most strains of the following organisms:
Proteus species (indole-positive and indole-negative) including:
Pr. mirabilis; Pr. morganii; Pr. rettgeri and Pr. vulgaris Escherichia coli
Klebsiella, Enterobacter, Serratia species Citrobacter species
Providencia species
Staphylococci, including Staph. aureus (coagulase-positive and coagulase-negative).
Aminoglycosides have a low order of activity against most Gram-positive organisms, including Streptococcus pyogenes, S. Pneumoniae and enterococci.
Some strains of Group D streptococci are susceptible in vitro although most strains of enterococci show resistance. In vitro studies have shown that an aminoglycoside combined with an antibiotic which interferes with cell wall synthesis affects some Group D streptococcal strains synergistically. The combination of benzylpenicillin and tobramycin results in a synergistic bactericidal effect in vitro against certain strains of S. faecalis. However, this combination is not synergistic against other closely related organisms, e.g. S. faecium. Specification of Group D streptococci alone cannot, therefore, be used to predict susceptibility. Susceptibility testing and tests for antibiotic synergism are emphasized.
Cross-resistance between aminoglycosides occurs and depends largely on inactivation by bacterial enzymes.
5.2 Pharmacokinetic properties
Absorption
Following intramuscular administration of a single dose of tobramycin 1 mg/kg in adults with normal renal function, peak plasma tobramycin concentrations averaging 4–6 micrograms/ml are obtained 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. Tobramycin is poorly absorbed from the gastrointestinal tract.
Distribution
After injection tobramycin has been detected in body fluids but concentrations in the cerebrospinal fluid are low even when there is meningeal inflammation. Most bodily compartments and tissues including the inner ear and kidneys become progressively saturated with aminoglycosides over the course of therapy, and the drug is slowly released from these areas. It has been postulated that this accumulation may account for the ototoxicity and nephrotoxicity associated with aminoglycosides. In general, aminoglycosides such as tobramycin readily cross the placenta. Small amounts of the drugs are also distributed into bile, saliva, sweat, tears, sputum, and milk.
Elimination
The major route of elimination is renal and the drug is eliminated almost entirely by glomerular filtration. Protein binding of tobramycin has been reported as zero. The plasma elimination half-life of tobramycin is usually 2–3 hours in adults with normal renal function and is reported to range from 5 to 70 hours in adults with impaired renal function. In full- term infants the plasma elimination halflife is reported to average 4.6 hours and in low birth-weight infants it averages 8.7 hours.
Peak urine concentrations ranging from 75 to 100 microgram/ml have been observed after the intramuscular injection of a single dose of 1 mg/kg. After several days of treatment, the amount of tobramycin excreted in the urine approaches the daily amount administered. When renal function is impaired, excretion of tobramycin is slowed, and accumulation of the drug may cause toxic blood levels. In patients undergoing dialysis, 25 to 70% of the administered dose may be removed, depending on the duration and type of dialysis.
5.3 Preclinical Safety Data
There are no preclinical data of relevance to the prescriber which are additional to the information already included in other sections of the SPC.
PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sodium metabisulphite
Disodium edetate
Sulphuric acid
Water for injections
6.2 Incompatibilities
Incompatibility or loss of activity has been reported between tobramycin sulfate and some cephalosporins and penicillins and also heparin sodium. Solutions with clindamycin phosphate in glucose injection are reported to be unstable.
Tobramycin Injection should not be physically premixed with other drugs but should be administered separately according to the recommended dose and route.
6.3 Shelf life
As packaged for sale –
40 mg/1 ml and 80 mg/2 ml presentations – 3years
240 mg/6 ml presentation – 2 years
After dilution –
Chemical and physical in-use stability has been demonstrated in dextrose 5% and sodium chloride 0.9% infusion solutions for 24 hours at 24°C in the presence of light.
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
As packaged for sale – Do not store above 25°C. Keep the vial in the outer carton in order to protect from light.
After dilution – see section 6.3.
6.5 Nature and Contents of Container
40 mg/1 ml and 80 mg/2 ml presentation – clear Type I glass vials with elastomeric stoppers in packs of 5 vials.
240 mg/6 ml presentation – clear Type I glass vials with elastomeric stoppers in packs of 1 or 5 vials.
Not all presentations above may be marketed.
6.5 Special precautions for disposal and other handling
6.5 Special precautions for disposal and other handlingSingle use only. Discard any unused contents.
When given by infusion, Tobramycin Injection may be diluted (with 0.9% Sodium Chloride
Intravenous Infusion BP or 5% Dextrose Intravenous Infusion BP) to volumes of 50–100 ml for adult doses.
Use in the paediatric population
For children, the volume of diluent should be proportionately less than for adults.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7 MARKETING AUTHORISATION HOLDER
Hospira UK Limited
Horizon
Honey Lane
Hurley
Maidenhead
SL6 6RJ
UK
8 MARKETING AUTHORISATION NUMBER(S)
PL 04515/0066
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
Date of first authorisation: 22/09/1993
Date of latest renewal: 26/02/2009