TOBRAMYCIN Solution for injection Ref.[7710] Active ingredients: Tobramycin

Posology

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 patient’s pre- treatment body weight should be obtained.

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

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 section 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.

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.

Elderly

As for adults, but see recommendations for patients with impaired renal function.

Paediatric population

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.

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.

Duration of treatment

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.

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.

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 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.

REGIMEN I – Reduced dosage at 8-hour intervals:

An appropriate reduced dosage range can be found in the accompanying table, (see 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, 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 section 4.4).

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

* For life-threatening infections, dosages 50% above those normally recommended may be used. The dosages should be reduced as soon as possible when improvement is noted.
° If used to estimate degree of renal impairment, serum creatinine concentrations should reflect a steady state of renal uraemia
† When dialysis is not being performed.

Method of administration

Precautions to be taken before handling or administering the medicinal product.

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 or 5% Dextrose Intravenous Infusion) 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 slowly 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 section 4.4).

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 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.

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.

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.

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.

Single 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.