Tobramycin Injection Bp 40 Mg/Ml And 80 Mg/2ml
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Tobramycin injection BP 40mg/ml and 80mg/2ml
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Tobramycin 1 ml / 2 ml
(in the form of Tobramycin Sulphate) 40.00 / 80.00 mg
3 PHARMACEUTICAL FORM
Injections for i.v. and i.m. use.
4. CLINICAL PARTICULARS
4.1. Therapeutic indications
Severe bacterial infections causative organism of which are sensitive to tobramycin. Tobramycin is effective against the following micro-organisms: E.coli, proteus strains, pseudomonas aeruginosa, Klebsiella, Enterobacter, Serratia, providencia, Citrobacter species and Staphylococcus.
Tobramycin is indicated for the treatment of the following infections caused by susceptible micro-organisms:
Infections of the lower respiratory tract (pneumonia, bronchopneumonia, bronchitis and bronchitis in association with cystic fibrosis;
Skin, soft tissue, muscle and bone infections, including complications of burns;
Urogenital infections (pyelitis, cystitis, pyelonephritis, epididymitis, prostatitis, adnexitis, infections of uterus and of the tissues around the uterus);
Gastrointestinal infections, including peritonitis;
Infections of the central nervous system including meningitis, septicaemia and neonatal sepsis;
Endocarditis (in this case tobramycin therapy should be supplemented with parentally administered penicillin or cephalosporin). If possible, microbiological tests should be made and antibiotic sensitivity should be determined prior to the therapy. In urgent cases the treatment can also be started without bacteriological results.
Laboratory testing for microbial susceptibility and for antibiotic synergism is emphasised. Cross resistance between aminoglycosides is largely dependent on inactivation by bacterial
enzymes. Tobramycin can be combined with other antibiotics to cause synergistic antibacterial effects:
- pseudomonas strains are generally susceptible to the combination of tobramycin and carbenicillin;
- Enterococcus faecalis of certain strains is susceptible to tobramycin and penicillin G;
- Other Gram-negative organisms may be synergistically treated by the combination of tobramycin and a cephalosporin.
4.2. Posology and method of administration
Route of administration:
i.m. injection i.v. injection
1. For adults with normal renal function, the recommended dosage is 1-1.5 mg/kg body weight 3 times a day i.v. or i.m.
2. For patients with impaired renal function, a single dose of 1 mg/kg body weight.
|
Serum creatinine |
Serum creatinine |
Creatinine clearance |
Dosage frequency |
|
mg % |
|j.mol/1 |
ml / min |
(hours) |
|
<1.3 |
<110 |
>80 |
8 |
|
1.4-1.9 |
110-168 |
40-80 |
12 |
|
2.0-2.8 |
176-247 |
25-40 |
18 |
|
2.9-3.7 |
256-327 |
15-25 |
24 |
|
3.8-5.3 |
335-468 |
10-15 |
36 |
|
5.4-7.2 |
477-636 |
5-10 |
48 |
|
> 7.2 |
>636 |
<5 |
72 |
3. In extremely obese patients the ideal body weight + 40% of the excess weight procedure the value on which correct dosage schedule should be based.
4. For infants and children the recommended dosage is 3-5 mg/kg/day in three equal doses.
5. In case of elderly patients, the creatinine clearance decreases by about 1 ml/min/year without any increase in serum creatinine conc. These changes result in a prolonged tobramycin excretion with a predictable accumulation if the usual dosage is administered.
6. In case of extensive burns the rate of glomelural filtration is increased with a subsequent increase in tobramycin elimination, therefore higher dose is recommended.
Serum concentrations should be monitored and regularly determined to achieve therapeutic serum levels in cases of
- life-threatening infections
- seriously impaired renal function
- changing renal function
- patients with hypacusis
- treatments for longer periods or with higher doses, than the average
- patients undergoing dialyses
The level necessary for therapeutic effect in severe infections is 7-10 mg/l, and in moderately severe infections is 4-7 mg/l.
Tobramycin can be administered i.v. and i.m. for 7-10 days. If necessary (e.g. in endocarditis it may be administered for 3-6 weeks along with continuous control.
In case of infusion administration, the single dose should be diluted with 100-200 ml of 0.9% Sodium Chloride or 5% glucose solution.
4.3. Contraindications
Intrathecal administration.
Hypersensitivity to any aminoglycoside: because of the cross-allergenicity of this class of drug.
4.4. Special warnings and precautions for use
Patients treated with Tobramycin should be under close clinical observation, because tobramycin and other aminoglycoside antibiotics have an inherent potential for causing ototoxicity and nephrotoxicity. Renal and eight 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 or auditory function requires discontinuation of the drug and dosage adjustment. The need for close monitoring of serum drug levels, renal function (including serum creatine or creatinine and electrolytes with urinalysis), and regular audiograms, patients with reduced renal function, dehydration receiving potent diuretics concomitant with high doses of tobramycin in chronic administration are especially vulnerable to adverse events.
During the treatment proliferation of non-sensitive micro-organisms may occur.
It 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.
The administration of tobramycin should be avoided in pregnant women unless the potential benefits definitely surpass the potential risk. In case the patient becomes pregnant during the administration of tobramycin or the drug is used during pregnancy, the patient should be notified of the potential foetal harm. Tobramycin, like other aminoglycoside antibiotics, crosses the placenta. Although in the case of other aminoglycosides no serious maternal or foetal harm has been reported so far, several cases with streptomycin have been reported in which total irreversible bilateral congenital deafness occurred in infants whose mothers were treated with streptomycin during pregnancy. Tobramycin should not be administered to nursing mothers either because it is excreted in the breast milk.
Aminoglycosides like tobramycin form a complex with beta-lactams. Therefore these drugs should not be mixed in the same syringe or infusion solution.
Furthermore see 4.9.
4.5. Interactions with other medicinal products and other forms of interaction
The toxicity of aminoglycosides, including tobramycin, is potentiated by the concurrent administration of cephaloridin, furosemid or etacynic acid in high doses and other potentially neurotoxic and/or nephrotoxic drugs. The effects of tubocurarine and succinylcholine, on the other hand, are potentiated by aminoglycosides, which may lead to respiratory paralysis. Aminoglycosides form a complex with beta-lactam antibiotics (tobramycin primarily with carbenicillin and ticarcillin) which may result in an interaction of attenuated effect. These drugs therefore should not be mixed in the same syringe or infusion solution.
In vivo interaction occur only in patients with impaired renal function when serum concentrations are increased.
4.6.
Pregnancy and lactation
The administration of tobramycin should be avoided in pregnant women unless the potential benefits definitely surpass the potential risk. In case the patient becomes pregnant during the administration of tobramycin or the drug is used during pregnancy, the patient should be notified of the potential foetal harm. Tobramycin, like other aminoglycoside antibiotics, crosses the placenta. Although in the case of other aminoglycosides no serious maternal or foetal harm has been reported so far, several cases with streptomycin have been reported in which total irreversible bilateral congenital deafness occurred in infants whose mothers were treated with streptomycin during pregnancy. Tobramycin should not be administered to nursing mothers either because it is excreted in the breast milk.
4.7. Effects on ability to drive and use machines
Aminoglycosides have a potential for causing ototoxicity both in cochlear and vestibular nerves. During Tobramycin therapy hearing decrease and vertigo may occur.
Until present we do not have any relevant data concerning the eventual effects of tobramycin on ability to drive and to use machines.
4.8. Undesirable effects
Side-effects are primarily due to overdosage. Aminoglycosides have a potential for causing ototoxicity both in cochlear and vestibular nerves. Ototoxicity is clinically manifested in hearing decrease and vertigo. The nephrotoxicity of tobramycin causes a decrease in the rate of glomerular filtration, while serum creatinine concentration and urea nitrogen are increased. In serious cases oliguria and anuria may also occur. 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. With correct dosage, however, the frequency of serious tobramycin side effects is below 1%.
Other reported adverse reactions include increased serum transaminase (SGOT, SGPT) and increased serum bilirubin, anaemia, leukocytopenia, thromocytopenia, and fever, rash itching, urticaria, vomiting, headache and lethargy.
4.9. Overdose
In case of overdosage (when serum concentration are higher than the average) or toxic reactions, peritoneal dialysis or hemodialysis will help remove tobramycin from the blood.
Signs of overdosage: oto and nephrotoxic signs, neuromuscular blockade, depressed respiration, myoparalysis, pseudomembranosus colitis.
In case respiratory paralysis resuscitation should immediately be started. Neuromuscular blockade may be reversed by the administration of calcium salts. Serum levels of tobramycin, fluid balance and creatinine clearance should be closely monitored until the serum tobramycin concentration decreases below 2 mg/ml. Between 25% and 70% of administered dose may be removed, depending on the duration and type of dialysis employed. Haemodialysis is the most effective.
5. PHARMACOLOGICAL PROPERTIES
5.1
Pharmacodynamic properties
Tobramycin is a broad-spectrum aminoglycoside antibiotic with relatively low toxicity. Although its toxicity is lower than that of most aminoglycosides (its therapeutic range is narrow) it is by no means negligible, and it should be administered with caution.
It has a potential for causing ototoxicity in cochlear and vestibular nerves.
The nephrotoxicity of tobramycin causes a decrease in the rate of glomerular filtration. These effects are mainly due to overdosage.
Tobramycin has a bactericide antibiotic effect due to its inhibition of protein synthesis. It has a broad-spectrum of antibacterial activity.
Antimicrobial activity of tobramycin:
Pseudomonas aeruginosa
Proteus species (indole-positive and indole-negative)
Morganella morganii Escherichia coli
Klebsiella-Enterobacter-Serratia species Citrobacter species Providencia species
Staphylococci, including Staphylococcus aureus (coagulase-positive and coagulase-negative) Moderate:
Enterococcus faecalis
5.2. Pharmacokinetic properties
The pharmacokinetical properties are similar to the other aminoglycosides.
It can be administered both i.m. and i.v.
Rapidly and fully absorbed from the injection site. Peak serum concentrations occur 45 and 90 minutes and reach 3 - 7 mg/l at a dose of 1 mg/kg body weight. In patients with normal renal function serum concentrations decrease to 2 mg/l within 8 hours. Plasma half-life is 2 hours.
Practically no protein bindings. The drug distributed in the extracellular space with an apparent volume of distribution approximately 20% of body weight.
Tobramycin is not metabolised. It is eliminated by glomerular filtration through the kidneys.
It is reabsorbed to some extent from proximal tubule. Peak urine concentrations range from 50 to 150 mg/l. Tobramycin is accumulated in the renal cortex with a concentration several hundred times higher as serum. It takes weeks to be eliminated from here.
Biliary excretion is minimal; without obstruction 25-80% of serum tobramycin conc. can be measured in bile. In case of obstruction or cystic valculus antibiotic conc. cannot be detected at all.
Tobramycin crosses the placental membranes and may reach a toxic concentration in the foetus.
Elimination of the drug is influenced by several factors, like:
- renal function: Renal function impairment leads to the prolongation of excretion. With a clearance of 10 ml/min the half life rises to 25-70 hours.
- age: Renal function is impaired with again between 20-90 year. Extensive burnsars endogen cratinine clearance decreases by about 1 ml/min/year.
- Extensive burns
5.3. Preclinical safety data
None stated.
6. PHARMACEUTICAL PARTICULARS
6.1. List of excipients
Sodium Metabisulphite,
Disodium Edetate Sulphuric Acid (10% solution)
Sodium Hydroxide (10% solution)
Water for injections
6.2. Incompatibilities
Aminoglycosides form a complex with beta-lactam antibiotics (tobramycin primarily with carbenicillin and ticarcillin) which may result in an interaction of attenuated effect. In vivo interactions occur only in patients with impaired renal function, when serum concentrations are high.
6.3. Shelf life
After opening the vial, it should be used immediately. The rest of the solution must not be used again.
Shelf-life: 5 years.
6.4. Special precautions for storage
Keep the product below 25°C, protected from light.
6.5. Nature and contents of container
The product is filled in 1 ml labelled glass ampoules. The type of ampoules is OPC in compliance with DIN ISO 9187 standard. The glass complies with the requirements for Type I glass.
Pack size 1 and 10 ampoules:
1 /5 ampoules are put in a blister and 1/2 blisters are placed into cardboard box together with Patient Information Leaflet. The product is compatible with the immediate packaging material.
Instruction for use/handling
6.6.
Aminoglycosides like tobramycin form a complex with beta-lactams. Therefore these drugs should not be mixed in the same syringe or infusion solution.
7 MARKETING AUTHORISATION HOLDER
Medimpex UK Ltd 127 Shirland Road London W9 2EP
8 MARKETING AUTHORISATION NUMBER(S)
PL 05276/0008
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
13/10/2005
10 DATE OF REVISION OF THE TEXT
13/10/2005