Hospira UK Ltd

4.2 Posology and method of administration
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Tobramycin Injection may be given intramuscularly or intravenously and the dosage is the same for either route of administration.  To calculate the correct dosage, the patients pre-treatment bodyweight should be obtained.

Patients with Normal Renal Function:-

Adults:

For adults with serious infections the usual recommended dosage is 3 mg/kg/day, administered in three equal doses every eight hours.

(see Table 1).

Patients with life-threatening infections, dosages up to 5 mg/kg/day may be administered in three or four equal dosages.  The dosage should be reduced to 3 mg/kg/day as soon as clinically indicated.  Dosage should not exceed 5 mg/kg/day, unless serum levels are monitored in order to prevent increased toxicity due to excessive blood levels.  (see 4.4).

It may be necessary to administer up to 8 to 10 mg/kg/day in equally divided doses, to achieve therapeutic serum levels for patients with cystic fibrosis.  Serum levels should be monitored because serum concentrations of tobramycin vary from patient to patient.

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. (see Table 1).

Table 1  Dosage schedule for adults with normal renal function

(Dosage at 8-hour intervals)

* Applicable to 40 mg/ml product forms.

The Elderly:

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 3 or 4 equally divided doses.  It may be necessary to administer higher doses in some patients.

Premature or Full-term Neonates:

Dosages of up to 4 mg/kg/day may be administered in two equal doses every 12 hours, for children between 1.5 and 2.5 kg body weight.

The usual length of treatment is seven to ten days.  However, in difficult and complicated infections, a longer course of therapy may be necessary.  In such cases monitoring of renal, auditory and vestibular functions is advised because neurotoxicity is more likely to occur when treatment is extended longer than ten days.

To ensure the correct dosage is given, it is recommended that blood levels should be determined whenever possible.  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 Impaired Renal Function

Following a loading dose of 1 mg/kg, subsequent dosage must be adjusted, either with lower doses administered at 8 hr intervals or with normal doses at prolonged intervals, (see Table 2).  Both these regimens are suggested as guides to be used when serum levels of tobramycin can not 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.

REGIMEN I - Reduced dosage at 8-hour intervals

An appropriate reduced dosage range can be found in the accompanying table, (Table 2) for any patient for whom the 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.  Another rough guide for determining reduced dosage at 8-hour intervals, e.g. 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/100 ml).

REGIMEN II - Normal dosage at prolonged intervals

Table 2 illustrates the recommended intervals between doses.  As a general rule, the dosage frequency in hours can be determined by multiplying the patient's serum creatinine level (expressed as mg/100 ml) 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 4.4).

Intramuscular administration:

Tobramycin Injection may be administered by withdrawing the appropriate dose directly from the vial.

Intravenous administration:

Tobramycin Injection may be given by intravenous infusion or by direct intravenous injection.  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.  For children, the volume of diluent should be proportionately less than for adults.  The diluted solution should be infused over a period of 20-60 minutes avoiding admixture with any other drug.  Tobramycin Injection may be administered by direct intravenous injection or into the tubing of a drip set.  When given in this way, serum levels may exceed 12 mg/litre for a short time. (see 4.4).

Table 2  Two maintenance regimens based on renal function and body weight following a loading dose of 1 mg/kg*

It is recommended that both peak and trough serum levels should be determined whenever possible to ensure the correct dosage is given.

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.

5.1       Pharmacodynamic properties

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Pharmacotherapeutic group: Aminoglycoside Antibacterials, ATC Code: J01G B01

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. Vulgarisvulgaris

                 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.

9        DATE OF FIRST AUTHORISATION/RENEWAL OF THE     AUTHORISATION

 DATE CHANGE

            22^nd September 199826/02/2009

10      DATE OF REVISION OF THE TEXT

DATE CHANGE

January 200826/02/2009

7.       MARKETING AUTHORISATION HOLDER

 Change to:

Hospira UK Limited

Queensway

Royal Leamington Spa

Warwickshire, CV31 3RW

United Kingdom

10.     DATE OF REVISION OF THE TEXT

                January 2008