Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Hospira UK Limited, Horizon, Honey Lane, Hurley, Maidenhead, SL6 6RJ, UK
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.
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 who develop cochlear damage may not have symptoms during therapy to warn 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.
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.
It is desirable to measure both peak and trough serum concentrations as high doses of drug may be associated with a greater risk of toxicity.
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 drug levels. Dosage must be based on measured serum levels in these patients.
Aminoglycosides may be absorbed in significant quantities from body surfaces for 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-type antibiotics (penicillins or cephalosporins) has been demonstrated in vitro and in patients with severe renal impairment. Such in activation 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. Use in Neonates:
Tobramycin should be used with caution and in reduced dosage in premature and full term neonate infants younger than 6 weeks of age because of their renal immaturity and the resulting prolongation of serum half-life of the drug.
Antibacterials: 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.
Aminoglycosides can cause foetal harm when administered to a pregnant woman. Aminoglycosides such as tobramycin cross the placenta and there have been several reports of total irreversible bilateral congenital deafness in children whose mothers received streptomycin during pregnancy. Although serious side effects to mother, foetus, or newborn have not been reported in the treatment of pregnant women with other aminoglycosides, 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.
Tobramycin is excreted in the breast milk and should be avoided in nursing women.
Not relevant.
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.
Hypersensitivity.
Fever, pain at injection site.
Rash, itching, urticaria, exfoliative dermatitis.
Nausea, vomiting, diarrhea.
Mental confusion and disorientation.
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:
United Kingdom: Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
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.
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