Posology : מינונים

4.2 Posology and method of administration
Amikacin sulphate injection may be given intravenously.

Amikacin should not be physically premixed with other drugs, but should be administered separately according to the recommended dose and route.

The patient's pre-treatment bodyweight should be obtained for calculation of correct dosage.

The status of renal function should be estimated by measurement of the serum creatinine concentration or calculation of the endogenous creatinine clearance rate. The blood urea nitrogen (BUN) is much less reliable for this purpose. Reassessment of renal function should be made periodically during therapy.

Whenever possible, amikacin concentrations in serum should be measured to assure adequate, but not excessive levels. It is desirable to measure both peak and trough serum concentrations intermittently during therapy. Peak concentrations (30-90 minutes after injection) above 35 mcg/ml and trough concentrations (just prior to the next dose) above 10 mcg/ml should be avoided. Dosage should be adjusted as indicated. In patients with normal renal function, once daily dosing may be used; peak concentrations in these cases may exceed 35 mcg/ml.

Intravenous administration
At the recommended dosage level, uncomplicated infections due to sensitive organisms should respond to therapy within 24 to 48 hours.

If clinical response does not occur within three to five days, consideration should be given to alternative therapy.

Adults and Children over 12 years
The recommended intravenous dosage for adults and adolescents with normal renal function (creatinine clearance ≥50 ml/min) is 15 mg/kg/day which may be administered as a single daily dose or divided into 2 equal doses i.e. 7.5 mg/kg q 12 h. The total daily dose should not exceed 1.5 g. In endocarditis and in febrile neutropenic patients, dosing should be twice daily, as there is not enough data to support once daily dosing.

Children 4 weeks to 12 years
The recommended intravenous (slow intravenous infusion) dose in children with normal renal function is 15-20 mg/kg/day which may be administered as 15-20 mg/kg, once a day; or as 7.5 mg/kg q 12 h. In endocarditis and in febrile neutropenic patients dosing should be twice daily, as there is not enough data to support once daily dosing.

Neonates
An initial loading dose of 10 mg/kg followed by 7.5 mg/kg q 12 h (see sections 4.4 and 5.2).

Premature Infants
The recommended dose in prematures is 7.5 mg/kg in every 12 hours (see sections 4.4 and 5.2).

The usual duration of treatment is 7 to 10 days. The total daily dose by all routes of administration should not exceed 15-20 mg/kg/day. In difficult and complicated infections where treatment beyond 10 days is considered, the use of amikacin sulphate injection should be reevaluated and, if continued, renal, auditory, vestibular function should be monitored, as well as serum amikacin levels.

If definite clinical response does not occur within 3 to 5 days, therapy should be stopped and the antibiotic susceptibility pattern of the invading organism should be rechecked.
Failure of the infection to respond may be due to resistance of the organism or to the presence of septic foci requiring surgical drainage.

Intravenous administration
The solution is administered to adults over a 30 to 60 minute period.

Specific recommendation for intravenous administration
In paediatric patients the amount of diluents used will depend on the amount of amikacin tolerated by the patient. The solution should normally be infused over a 30 to 60 minute period. Infants should receive a 1 to 2 hour infusion.

Elderly
Amikacin is excreted by the renal route, renal function should be assessed whenever possible and dosage adjusted as described under impaired renal function.

Life-threatening infections and/or those caused by pseudomonas

The adult dose may be increased to 500 mg every eight hours but should never exceed 1.5 g/day nor be administered for a period longer than 10 days. A maximum total adult dose of 15 g should not be exceeded.

Urinary tract infections: (other than pseudomonas infections)
7.5 mg/kg/day in two equally divided doses (equivalent to 250 mg b.i.d. in adults). As the activity of amikacin is enhanced by increasing the pH, a urinary alkalinising agent may be administered concurrently.

Impaired renal function
In patients with renal impairment reflected by creatinine clearance less than 50 mL/min, administration of the recommended total daily dose of amikacin in single daily doses is not desirable since these patients will have protracted exposure to high trough concentrations. See below for dosage adjustments in patients with impaired renal function.

For patients with impaired renal function receiving usual twice or three times daily dosing, whenever possible, serum amikacin concentrations should be monitored by appropriate assay procedures. Doses should be adjusted in patients with impaired renal function either by administering normal doses at prolonged intervals or by administering reduced doses at fixed intervals.

Both methods are based on the patient's creatinine clearance or serum creatinine values since these have been found to correlate with aminoglycoside half-lives in patients with diminished renal function. These dosage schedules must be used in conjunction with careful clinical and laboratory observations of the patient and should be modified as necessary, including modification when dialysis is being performed.

Normal Dose at Prolonged Intervals Between Dosing:
If the creatinine clearance rate is not available and the patient's condition is stable, a dosage interval in hours for the normal single dose (ie, that which would be given to patients with normal renal function on a twice daily schedule, 7.5 mg/kg) can be calculated by multiplying the patient's serum creatinine by nine; e.g., if the serum creatinine concentration is 2mg/100mL, the recommended single dose (7.5 mg/kg) should be administered every 18 hours.

Serum Creatinine                           Interval between Amikacin doses of 7.5 Concentration                              mg/kg
(mg/100 ml)                                IM (hours)
1.5                                        13.5
2.0                                        18.0
2.5                                        22.5
3.0                                        27.0
3.5                           X9=          31.5
4.0                                        36.0
4.5                                        40.5
5.0                                        45.0
5.5                                        49.5
6.0                                        54.0
As renal function may alter appreciably during therapy, the serum creatinine should be checked frequently and the dosage regimen modified as necessary.

Reduced Dose at Fixed Time Intervals Between Dosing:
When renal function is impaired and it is desirable to administer amikacin sulfate injection at a fixed time interval, dose must be reduced.
In these patients, serum amikacin concentrations should be measured to assure accurate administration and to avoid excessive serum concentrations. If serum assay determinations are not available, and patient's condition is stable, serum creatinine and creatinine clearance values are the most readily available indicators of the degree of renal impairment to use as a guide for dosage.

First initiate therapy by administering a normal dose, 7.5 mg/kg, as a loading dose. This dose is the same as the normally recommended dose which would be calculated for a patient with a normal renal function as described above.
To determine the size of maintenance doses administered every 12 hours, the loading dose should be reduced in proportion to the reduction in the patient's creatinine clearance rate:


(CrCl = creatinine clearance rate)
An alternate rough guide for determining reduced dosage at 12-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.

The above dosage schedules are not intended to be rigid recommendations, but are provided as guides to dosage when the measurement of amikacin serum levels is not feasible.